TW201103897A - Purification method of mycophenolic acid and method for preparing high purity sodium mycophenolate using the same - Google Patents

Abstract

This invention relates to a purification method of mycophenolic acid and preparation of high purity sodium mycophenolate. The mycophenolic acid to be purified is converted into a mycophenolic acid ester derivative and through the differences in physical property between the mycophenolic acid and mycophenolic acid ester derivative, the impurities in the mycophenolic acid that was hard to remove is reduced. After the purified mycophenolic acid ester derivative undergoes hydrolysis reaction in a sodium hydroxide aqueous solution and is performed with steps of acidification, extraction, concentration and re-crystallization, the mycophenolic acid is obtained, wherein the content of the impurities is far below 0.10%. The sodium mycophenolate is the prodrug of mycophenolic acid, and in the preparation condition of the sodium mycophenolate, the purity of mycophenolic acid has crucial influences on the quality of the sodium mycophenolate product. The purified mycophenolic acid and sodium-containing organic alkaloid or inorganic alkaloid are performed with the saponification reaction the sodium mycophenolate is obtained, wherein the content of the impurities is far below 0.10%.

Description

201103897 VI. Description of the invention: [Technical field to which the invention belongs] The chemical structure of mycophenolic acid is as follows:

Mycophenolic acid is an immunosuppressant used for organ transplantation to prevent organ recipients from rejecting newly implanted organs. The mycophenolic acid hypoxanthine monophosphate dehydrogenase (IMDH) inhibitor can inhibit lymphatic tau cells by controlling the purine re-synthesis (ie, v〇synthesis) pathway. Activated proliferation of B cells. In addition, mycophenolic acid also has antitumor, amifimal, antibacterial, and antivirai properties (see patent US 2008/0293110 A1 and references and patents cited herein) ). [Prior Art] In the patent US 2008/0293110 A1, a method for the separation of moldy acid is disclosed, which is mixed with a fermentation broth by an appropriate test, and after being mixed and filtered, it is acidified, crystallized, and passed through. After the obtained acid test, after purification by toluene, the purity can reach 99.2%. 3 201103897 In the patent WO 2009/040828 A1, a method for purifying mycophenolic acid is disclosed, which first extracts a polar impurity in a solution of mycophenolic acid in an ethyl acetate solution using a low volume molar aqueous solution of sodium carbonate; After that, the extract of mycophenolic acid in ethyl acetate was continuously extracted with an aqueous solution of sodium hydroxide; the combined sodium hydroxide extract was extracted with n-butanol to extract non-polarity in the ethyl acetate solution of mycophenolic acid ( Non_polar) of impurities. The extracted aqueous sodium hydroxide solution is acidified, extracted, and re-agglomerated in an organic solvent to obtain purified mycophenolic acid; in the example (1) of this patent, the yield is 60%, wherein mycophenolic acid The highest impurity content is 0.12%; in the embodiment (2), the yield is only 50%, wherein the amount of impurities in the mycophenolic acid is between 0.10 and 0.12%; in the embodiment (3), Although the rate can reach 80% 'but, there are still several impurities in the mycophenolic acid content between 〇1〇~〇13〇/〇. Although, according to the purification method disclosed in the patent WO 2009/040828 A1, the obtained mycophenolic acid has a purity higher than that published in the patent US 2008/0293110 A1, but 'the content of the individual impurities contained therein is still higher than 〇1. 〇% of the boundary range of the repair "according to the 1CH guidelines (ICH guidelines), where the individual impurities are greater than 〇.1〇〇 / 0 or more, they must be separated and structurally identified, therefore, this method is still not ideal purification method. SUMMARY OF THE INVENTION According to the mycophenolic acid (1) 'system through the fermentation process, using the general organic solvent re-cure method, can not effectively reduce the impurities produced by the mycophenolate mofetil (located in RRT 〇.83 , 3.65, 5.73, 5 87, 6 〇 3 ). However, in the wounding conditions of the prodrug sodium salt (1) of mycophenolic acid (1) 4 201103897, the purity of the acid (1) has an absolute influence on the quality of the sodium salt. In the present invention, the mold is converted into a mildew-_derivative, and the difference in physical properties between the sulphate acid and the _acid is _yield which is difficult to remove in the mold. The obtained mildew derivative is subjected to a hydrolysis reaction in a water of a metal hydroxide (a brain hydroxide); a step of acidification, extraction, concentration, re-knotification, etc. to obtain a mycophenolic acid, a towel thereof, The content of impurities is much lower than 〇1〇%, and the yield is 86.5%. After the purified mycophenolic acid is saponified with a sodium-containing organic or inorganic base, a high-purity sodium sulphate salt can be obtained, wherein the content of the impurities is much lower than 〇] 〇 % or less. The present invention utilizes an esterification reaction to convert the mycophenolic acid (1) to be purified into a mycophenolate derivative (3), as shown in the scheme, using mycophenolic acid (1) and mycophenolic acid. The difference in physical properties between the acid ester derivatives (3) reduces the impurities which are not easily removed in the mycophenolic acid (1). After the purified mycophenolate ester derivative (3) 'hydrolyzed in an aqueous alkali metal hydroxide solution, the mycophenolic acid (1) is obtained by acidification, extraction, concentration, re-cylinder, etc., wherein the impurity (Located at RRT 0.83, 3.65, 5.73, 5.87, 6.03) are well below 〇.10%. 5 201103897

Process 1

3b: R=CH2〇H3 3c: R=CH2CH2CH3 3d: R=CH(CH3)2

3e: R=CH, CH, -|^〇

Hydrolysis | Hydrolysis

The mycophenolic acid (1) purification process of the present invention comprises the following combination of reaction and process (戋 step): (1) vineification reaction of alcohol (alcohol) (4) with mycophenolic acid (1) in organic acid Under the catalysis of Wra-toluenesulfonic acid (p-TSA) (5), the esterification reaction produces 'alkyl mycophenolate (3a-d), mycophenolate The ester (3a-d) can be obtained by precipitation in an alcohol (4) solution. Further, the obtained mycophenolate derivative (3) can also be re-purified in the alcohol (4); and the mycophenolate derivative after re-purification in the alcohol (4) (3) ), the purity of mycophenolic acid produced after hydrolysis can be more effectively improved. The invention converts the mycophenolic acid (1) to be purified into the mycophenolate ester derivative (3), and utilizes the physical property between the mycophenolic acid (D and the mycophenolate ester derivative (3). The difference 'reduced the impurities that were not easily removed in the soy acid (1). However, there are 6 201103897 some alcohol molecules are too large, such as 2 · (4- morphine) ethanol (2_(4_m()rph()linyl) )ethan()1) (6) 'The esterification reaction cannot be directly carried out with mycophenolic acid (1). Therefore, after changing the mycophenolate mofetil) to the mold test acid (S), (3a-d), The transesterification reaction is carried out to obtain the desired ester derivative, and the reaction is shown in Scheme 1. 2-(4-Merlin) ethanol (6) and mycophenolate (3a_d) are transesterified in terpene benzene under the catalysis of dibutyltinoxide. • Produce mycophenolic acid 2_ ( 4_morpholine)ethyl ester (3e). The resulting mildew acid 2-(4·Merlin) ethyl vinegar (3e) is dissolved in the water layer after acidification, and can be effectively removed by extraction with an organic solvent such as ethyl acetate (1) ) Impure that is not easy to remove. After the hydrolysis, the organic solvent extraction, concentration, and drying of the mycophenolic acid 2-(4-loryl)acetic acid (3e), high-purity mycophenolic acid can be obtained after hydrolysis. _ (2) hydrolysis reaction of mycophenolate derivatives (3) Mycophenolate derivatives (3) are hydrolyzed in an aqueous alkali metal hydroxide solution, followed by acidification, extraction, condensation, and further In the step of knotting, a mycophenolic acid (1) is obtained, wherein the content of the 'impurity is far below 0.10 〇 / 〇. In the hydrolysis of the mycophenolate derivative (3), the amount of the alkali metal hydroxide can be most suitably determined by the LOW equivalent of 3. 〇 to Μ. The metal oxide can be a hydroxide, sodium hydroxide or potassium hydroxide, of which sodium is most suitable for gas oxidation. The reaction time can be from 2 to 36 hours to 4 to 24 hours. After the acidification of the reaction solution, the pH of 7201103897 can be 0.3~3.5, and 0.5~2·0 is most suitable. The invention utilizes the difference in physical properties between the mycophenolic acid (1) and the mycophenolic acid vinegar derivative (3) to reduce the impurities which are not easily removed in the moldy acid, so as to obtain high quality and low impurity content. Mycophenolic acid (1). The refining of the mycophenolate ester derivative (3) in the alcohol (4) can further improve the purity of the mycophenolic acid (1)' produced after the hydrolysis, and the mycophenolate molybdenum ( 3a-d) and 2_(4-morpholine)ethanol (6)' After the transesterification reaction, the resulting mycophenolic acid 2-(4-morpholine)ethyl ester (3e)' can be obtained after hydrolysis. The purity of mycophenolic acid (1) 'where the impurities are less than 0.05%. In addition to the impurities produced by the fermentation process, the mild acid (^) in the purification process filtered through celite often has a deep purple color which is not easily removed by general organic solvents. In the present invention, p-toluenesulfonic acid (5) is used, and it is mixed with a re-synthesis solution of mycophenolic acid (1), and after crystallization and filtration, a white fungus phenolic acid # (1) solid can be obtained. In the re-junction process of the organic solvent of mycophenolic acid (1), the amount of p-toluenesulfonic acid (5) used may be G.GG1 to G.2G equivalent, and the most suitable one is _2 to q15 equivalent. In the preparation conditions of the prodrug sodium salt (1) of the mycophenolic acid (1), the purity of the mycophenolic acid (1) has a decisive influence on the quality of the solubilized sodium salt (1). The purified oxalic acid (1) is reacted with the organic-containing or non-mineralized 4-carbonated sodium salt (2), wherein the content of the impurities is much lower than 〇1〇%. 8 201103897 [Embodiment] The present invention can be illustrated by the following embodiments, but the scope of the present invention is not limited to the embodiments described below. In the reactions described in the following examples, the reaction starting materials, intermediates and products were analyzed by high performance liquid chromatography (HPLC, Waters). The analytical conditions of the high performance liquid chromatography were as follows. :

1. Column (Column). ZORBAX, 150 X 4.6 mm, Agilent C8 2. Column temperature: 45 ° C 3. Mobile phase: Mix 350 ml of acetonitrile (nit〇nitrile), 650 ml of pure water and 2.0 ml of triethylamine, the pH of the mixed solution was adjusted to 5.3 with 85% aqueous acid solution, and used after shaking. 4. Flowrate: 0.8 mL/min. 5. Detection wavelength: 250 nm

6. Injection volume: 10 uL Under these conditions, the impurities displayed by the liquid chromatograph showed a relative retention time (RRT) with an error range of -0.05 to +0.05. between. Example 1 (0 Methyl Mycophenolate) Methyl Mycophenolate was added to the reaction flask (9.5 g, 29.7 mmol), wherein the impurities were at RRT 0.83, 3.65, 6.03, respectively, 〇_16%. 0.54%, 0.54%) and 9 201103897 methanol (250 ml), the reaction mixture was stirred at room temperature to a clear solution, and p-toluene (0.42 g, 2.4 mmol) was added. The reaction solution was heated to reflux and stirred for 2 hours. Distilled methanol (15 〇ml) under ten pressures, cooled and crystallized, the liquid temperature reached 25. When it was cooled, it was cooled in an ice water bath, and filtered at the liquid temperature. The bottle wall and the wet solid were washed with ice methanol, and the solid was 60. C dried to give a white solid product (9·4 g, 28.0 mmol), yield 94.4%. (2) Hydrolysis of methyl mycophenolate. Add sodium hydroxide (3 8 g) to the reaction flask at room temperature. , 95 〇 millimolar) and pure water (pen liter) 'mix the mixture to a clear aqueous solution. Add the mycophenolate ester (9.0 g 27.0 mmol), and mix for 21 hours at the temperature. The reaction solution is acetic acid B. The ester (1 ml) was extracted and the organic layer was discarded. The aqueous layer was adjusted with 32% aqueous hydrochloric acid. The value was reduced to 丨5 and extracted twice with ethyl acetate (10 ml). Combined with ethyl acetate vinegar solution, steaming cranes under normal pressure to produce acetic acid B. ((0 ml) 'cooling and crystallization, when the liquid temperature reaches the pit, cool with ice water bath' and filter at the liquid temperature rc 'bottle wall and seat solids to ice The acetic acid was washed with acetic acid and dried at 60 C to obtain a white solid product (79 g, 24 7 mmol), wherein the impurities were located at RRT 0.83, 3·65, 6. G3 were respectively G.G5%, 〇 〇3%, 0.02%), yield 91.6% 〇Example 2 (1) Synthetic methyl mycophenolate was added to the reaction flask with mycophenolic acid (3 〇. gram, 93 8 mmol, of which impurities Located at RRT O.83, 3.65, π content is 〇2〇%, 〇s6%, 〇42%) 201103897 with methanol (150 ml) 'The reaction mixture is stirred at room temperature to a clear solution, and added to the 曱 曱 曱Acid (1.26 g '7.3 mmol). The reaction solution was heated to reflux and spoiled for 2 hours. The crystal was cooled and cooled, and cooled in an ice water bath at room temperature, and the liquid temperature was 2. After filtration, the wall and wet solid were washed with ice-cold alcohol, and the wet solid was dried at 60 ° C to give a white solid product (28.8 g, 86.2 mmol), yield 95.2%. (2) Synthetic mold acid 2- (4-Merlin) ethyl vinegar was added to the reaction flask with methyl mycophenolate (2 〇. gram, 59.9 mmol), toluene (74 4 • gram), 2- (4-Merlin) Ethanol (8.3 g '63.1 mmol) and 2-butyltin oxide (1.5 g, 6_0 mmol), the reaction mixture was heated to reflux and stirred for hr. The temperature was lowered and the temperature was 46 in the reaction solution. (:, adding 2-butyltin oxide (6.0 g, 24.0 mmol)), heating the reaction mixture to reflux, stirring at reflux temperature for 4 hrs. Cooling, reaction; when the internal temperature of the solution is 48 ° C, Add activated carbon (1. g), and mix for j hours. Add ethyl acetate (22.9 g), stir for 5 minutes, then pass through celite (ceUte), and wash the bottle wall with ethyl acetate (22.9 g) Collect and combine the mash and the washing liquid, and wash it with pure water (45.8 g). Mix the organic solution with pure water (45 8 g), fresh, adjust the pH to 162 with 32% hydrochloric acid aqueous solution, and let stand. The organic layer was discarded, and the aqueous layer was washed twice with ethyl acetate (45.8 g). The aqueous layer was mixed with the second gas (6 4 g), stirred, and then adjusted to pH 1 with 45% aqueous sodium hydroxide. 〇83, static layering' The organic layer was collected, and the water layer was extracted with two gas (61.4 g), and the organic layer was combined and washed with saturated water. The layer was concentrated to dryness, and the solid matter was 6 〇. After drying, 'solid product (2). 5 g, 49 6 mmol) was obtained, yield 82 8 〇 / 〇. (3) Molybdenum acid 2- (4-Merlin) B hydrolysis of 201103897 At room temperature 'In the reaction bottle, add sodium hydroxide (32 g, 78 8 mmol) and pure water (100 ί l), disturb the mixture to a clear aqueous solution. Methyl vinegar 2 (4, _ _ _ _) vinegar (10.0 g, 23.1 mmol) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was extracted twice with ethyl acetate (9 ml), and then the organic layer was evaporated, and the aqueous layer was mixed with ethyl acetate (100 ml) and stirred to adjust the pH value to 136 with a 32 〇/〇 aqueous hydrochloric acid solution, and allowed to stand for stratification. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (50 liters). The ethyl acetate solution was combined, and ethyl acetate (140 ml) was distilled off under normal pressure, and the crystals were cooled and crystallized. When the liquid temperature reached 25 ° C, it was cooled in an ice water bath and the liquid temperature was 2. When the time was over, the bottle wall and the sputum solid were washed with glacial acetic acid acetonitrile, and the solid was solidified at 6 (rc lin) to give a white solid product (69 g, 21.6 mmol), wherein the impurities were located at RRT 〇83, 3 65, 5 The content of 73 was 0.03%, <0.01%, 0.01%, respectively, and the yield was 93.5%. Example 3 Mycophenolic Acid Decolorization Purple Mycophenolic Acid (30.0 g, 93.8 mmol) and acetone (150 ml) φ Mix and stir in the reaction flask, add p-benzoic acid (0.62 g, 3.6 mmol). Heat the mixture to reflux (purple disappears, the solution is pale yellow). Decrease the crystal, ice at room temperature The water bath is cooled and the liquid temperature is 2. (: Filtered, the wall of the bottle and the wet solid are washed with ice, and the wet solid is dried at 60 ° C to obtain white mycophenolic acid (24 g, 75 mmol). The rate was 80%.Example 4 Preparation of mycophenolate sodium salt Mycophenolic acid (5 g, 15.63 mmol) was added to the reaction flask, wherein the impurity 12 201103897 was located at RRT 0.83, 3.65, respectively, 〇.〇5% , 〇, 〇ι%), sodium hydroxide (0 625 g ' 15.63 mmol) and decyl alcohol (1 〇〇 ml), heating the reaction mixture to After stirring for 0.5 hour, decyl alcohol (70 ml) was distilled off, and the temperature was lowered at a liquid temperature of 26. At the time of hydrazine, isopropanol (70 ml) was added to heat the mixture to reflux, and methanol/isopropanol was distilled off. Liquid (70 ml), cooled, filtered at a liquid temperature of 24 ° C, the wall of the bottle and the wet solid were washed with isopropyl alcohol, and the wet solid was dried at 60 ° C to obtain a solid product, mycophenolate sodium salt (5.12 g, 14.97).亳莫耳, in which the impurity is located in the shape of Ding, the Φ content of 3 65 is 0.04%, <0.01%), the yield is 95.8%. Preparation of iSMl mycophenolate sodium salt (comparative process) in the reaction bottle Mycophenolic acid (5 g, 15.63 mmol) was added, wherein the impurities were located at RRT 0.83, 3.65, 5.87, respectively, 〇.ΐ7〇/ό, 〇.56%, 0.48%), sodium hydroxide (0.625 g) , 15.63 millimolar) and decyl alcohol (100 ml), the reaction mixture was heated to reflux, stirred for 0.5 hours, then 'distilled methanol (7 mL). Cooling, ® was added isopropanol at a liquid temperature of 28 ° C ( 70 ml), heat the mixture to reflux, and distill off the decyl alcohol/isopropanol mixture (70 ml). The temperature was 25. When filtering, the bottle wall and the wet solid were washed with isopropyl alcohol, and the wet solid was dried at 60 Torr to obtain a solid product, mycophenolate sodium salt (4.8 g ' 14.04 mmol, wherein the impurity was located at rrto 83, The content of 3.65, 5.87 is 0.13%, 0.04%, 0.04%), and the yield is 89.8%. The content of the impurity of the mycophenolic acid or the mycophenolic acid salt prepared by the invention may be as low as 0.05% or less and less than 0.05%. 'It is far superior to the aforementioned prior art (pri〇r _) of the impurities 201103897 higher than 0.10%. [Simple diagram description] None [Main component symbol description] None

Claims (1)

201103897 VII. Scope of application: 1. A method for purifying the acid, comprising the following steps: A. esterifying the acid with an alcohol to obtain a mycophenolate ester or an acid ester derivative thereof; The mycophenolate acid ester or its acid ester derivative is subjected to a hydrolysis reaction to obtain a high-purity mycophenolic acid. 2. The method of claim 1, wherein the mycophenolate acid ester or the acid ester thereof is subjected to a hydrolysis reaction, wherein the acid vinegar or the acid vinegar derivative thereof is used in the aqueous metal hydroxide solution. The hydrolysis reaction carried out. 3. The method of claim 2, wherein the alkali metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide. 4. A method for purifying mycophenolic acid, which is effectively removed by an organic acid when the mycophenolic acid exhibits a deep purple color which is generally difficult to remove during the purification process. φ 5. The method of claim 4 of the May patent scope wherein the organic acid is p-p-phenylene acid. 6. A method for preparing high-purity mold riding (4), which is ordered by the patent application scope! The 8 purity #_ obtained in the item is reacted with a touch or no saponification to obtain a high-purity sodium salt of high acidity. 7. If Shen (7) specializes in her method of item 6, wherein the high-purity sodium salt of silk, the content of all the individual impurities of the Xanthoxylum soda salt is reduced to _% or less than 0.05%. . 15 201103897 4. Designation of representative drawings: (1) The representative representative of the case is: ( ). (2) A brief description of the symbol of the representative figure: None 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: [Embodiment] The present invention can be illustrated by the following embodiments, but the scope of the present invention is not limited to the embodiments described below. In the reactions described in the following examples, the reaction starting materials, intermediates and products were analyzed by high performance liquid chromatography (HPLC, Waters). The analytical conditions of the high performance liquid chromatography were as follows. : 1. Column: ZORBAX, 150x4.6 mm, Agilent C8 2. Column temperature: 45 °C 3. Mobile phase: Mix 350 ml of acetonitrile, 650 ml of pure water and 2.0 Triethylamine (triethylamine), the pH of the mixed solution was adjusted to 5.3 with 85% aqueous acid solution, and used after shaking. 4. Flowrate: 0.8mL/min. 5. Detection wavelength · · 250 nm 6. Injection volume: 10uL Under these conditions, the impurities displayed by liquid chromatography are analyzed for their absorption peaks. The relative retention times (RTT) have an error ranging from -0.05 to +0.05. Example 1 (1) Synthesis of methyl mycophenolate (Me%l Mycophenolate) Mycophenolic acid (9·5 g, 29.7 mmol) was added to the reaction flask, wherein the impurities were at RRT 0.83, 3.65, 6.03, respectively. 〇16〇/〇, 〇54〇/〇, 〇54%) and 9 201103897 methanol (25〇ml)' Stir the reaction mixture to a clear solution at room temperature, add -toluene κ C (X42 g ' 2·4 Millions of ears). The reaction solution was heated to reflux and searched for 2 hours. Atmospheric pressure of methanol (150 ml), cooling and crystallization, liquid temperature up to 25. (: When the cold water is cold and cold, and the liquid temperature is 2. When filtering, the bottle wall and the solid solid are iced methanol, first _ Lai body to the machine money, to get white miscellaneous products (9 4 grams, then Momo ), 'yield 94.4%. (2) hydrolysis of myristic acid vinegar 〇i temperature' Add sodium hydroxide (3.8 g, 95.0 mmol) to pure water (100 ml) in the reaction flask. To clear the aqueous solution. Add the myristic acid methyl vinegar (9. gram '27.0 mmol) to stir at room temperature for 21 hours. The reaction solution was extracted with ethyl acetate (10 ml) to discard the organic layer. The water layer was 32%. The aqueous solution of hydrochloric acid was adjusted to pH 15 and extracted twice with ethyl acetate (100 ml). The ethyl acetate solution was combined, and the acetic acid was evaporated under reflux (170 liters) to reduce the temperature and crystallize. The mixture was cooled in an ice water bath and washed at a liquid temperature of 1 c. The mixture was washed with glacial acetic acid, and dried at 60 ° C to give a white solid product (7.9 g, 247 mmol). The impurities were located at RRT 0.83, 3.65, and 6.·3 were 〇〇5%, 〇〇3%, 0.02°/.), and the yield was 91.6%. Example 2 (1) Synthetic methyl mycophenolate was added to the reaction flask to add mycophenolic acid (3 〇. gram, 93 8 mmol), wherein the impurities were located at RRT 0.83, 3.65, 5.73, respectively. %, 〇56%, 0.42%) 201103897 With methanol (150 ml), the reaction mixture was stirred at room temperature to a clear solution, and p-methylsulfonic acid (1.26 g, 7.3 mmol) was added. The reaction solution was heated to reflux. Stir for 2 hours, cool down and crystallize, cool in an ice water bath at room temperature and filter at a liquid temperature of 2 ° C. The bottle wall and wet solid are washed with ice methanol, and the wet solid is dried at 60 ° C to obtain a white solid product ( 28.8 g, 86.2 mmol, yield 95.2%. (2) Synthetic mycophenolate 2-(4-morpholine)ethyl ester was added to the reaction flask with decyl phenolate (20.0 g, 59.9 mmol) Toluene (74,4 gram), 2-(4-morpholine)ethanol (8.3 g, 63.1 mmol) and 2-butyltin oxide (1.5 g, 6.0 mmol) were heated to reflux. Stir for 1 hour. Cool down, add 2-butyltin oxide (6.0 g, 24.0 mmol) to the reaction solution at an internal temperature of 46 ° C. The mixture was refluxed at reflux temperature for 4 hours. When the temperature was lowered at 48 ° C, the activated carbon (1.0 g) was added and stirred for 1 hour. Ethyl acetate (22.9 g) was added and stirred. After a minute, celite was filtered, the wall of the bottle was washed with ethyl acetate (22.9 g), and the filtrate and washing solution were collected and mixed, and Q was washed with pure water (45·8 g). Water (45.8 g) was mixed and stirred, and the pH was adjusted to 162 with a 32% aqueous hydrochloric acid solution, and the mixture was allowed to stand, and the organic layer was discarded, and the aqueous layer was washed twice with ethyl acetate (45.8 g). Mix the water layer with the two gas (4).4g), stir and adjust the pH to 1〇83 with 45°/〇 sodium hydroxide solution, let stand for layering, collect the organic layer 'water layer to two gas The mixture was fired (614 g), and the combined organic layers were washed with saturated aqueous sodium. The organic layer was concentrated to dryness. (10) The residue was dried at <RTI ID=0.0>>>>> (3) Hydrolysis of 2- (4-Merline) B. 201103897 Stirring mixture of sodium hydroxide (3.2 g, 78.8 mmol) and pure water (100 ml) was added to the reaction flask at room temperature. To clear the aqueous solution. 2- (4-morpholine)ethyl mycophenolate (10.0 g, 23.1 mmol) was added and stirred at room temperature for 4 hours. The reaction solution was extracted twice with ethyl acetate (50 mL). The organic layer was evaporated, and the aqueous layer was mixed with ethyl acetate (1 ml) and stirred, and adjusted to pH 136 with a 32% aqueous hydrochloric acid solution. The organic layer was collected and the aqueous layer was extracted ethyl acetate (5 mL). Combined with acetic acid ethyl s solution, steamed crane to ethyl acetate (14G ml) under normal pressure, and cooled and crystallized. When the temperature of the mash is reached, it is cooled in an ice water bath and filtered at a liquid temperature of 2 ° C. Drying with wet solids in EtOAc (br.) washed with EtOAc EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 0.01%, 0.01%), yield % 5%. Example 3 Mycophenolic Acid Decolorization I Mix purple mycophenolic acid (30.0 g, 93.8 mmol) with acetone (15 ml) 1 in a reaction flask, mix and mix, and add p-benzoic acid (〇 62 grams, 3 6 millimoles). The mixture was heated to reflux (purple disappeared and the solution was pale yellow). Cooling and crystallization, cooling in an ice water bath at room temperature, and filtering at a liquid temperature of 2 ,, the nucleus and the surface body are washed with ice-acrylic mesh, and the solid is dried at 60 C to obtain white moldy acid (24 g, 75 亳 mo Ear), yield 80%. Example 4 Preparation of Mycophenolate Sodium Salt In the reaction bottle, t was added to the mold (5 g, 15 63 mmol, wherein the impurity 201103897 was located at RRT 0.83, and the content of 3.65 was 〇·〇 5%, respectively. 〇1%), sodium oxynitride (〇 gram ' 15.63 mmol) and methanol (10 ml), the reaction mixture was heated to reflux, stirred for 5 hours, and then evaporated to methanol (7 mL). The temperature was lowered. When the liquid temperature was 耽, isopropanol (70 ml) was added, and the mixture was heated to reflux and evaporated to give a methanol/isopropyl chloride solution (7 ml). Cooling 'in liquid temperature is 2 (C when the sputum, bottle wall and wet solid 豸 瞒 ' ' 观 观 观 观 观 观 ' 得 得 得 得 得 得 得 得 得 得 得 得 得 盼 盼 盼 盼 盼 盼 盼 盼 盼 盼 盼 盼 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 The amount of 0 at 65 was 0.04%, <0.01%, respectively, and the yield was 95.8%. Example 5 Preparation of Mycophenolate Sodium Salt (Comparative Process) Mycophenolic acid (5 g, 15 63) was added to the reaction flask. Milliohms, wherein the impurities are located at RRT 0.83, 3.65, 5.87, respectively, 〇.17%, 〇56%, 〇48%), sodium oxynitride (0.625 g '15.63 mmol), and methanol (ML) Heat the reaction mixture to reflux, stir for 5 hours, distill off methanol (7 mL). Cool down, add the beer (70 $L) to the liquid temperature & machine, heat the mixture to reflux, and steam. Methanol / isopropanol mixture (7 〇 ml). Cool down, filter when the liquid temperature is pit, wash the bottle wall and wet solid with isopropyl alcohol, wet solid at 6 〇. Dry to obtain solid product mycophenolic acid Sodium salt (4.8 g, 14.04 mmol), wherein the impurities are located at rrt 0.83, 3.65, 5.87, respectively, 〇13%, 〇〇4%, 〇 〇4%), yield 89 8%. The mycophenolic acid or mycophenolate sodium salt prepared by the invention may have an impurity content as low as 0.05 ° / ❶ or less than 0.05% 'far better than the aforementioned prior art (pri 〇rarts)