Purification method of 11 beta, 17 alpha-dihydroxy-6-methyl-1, 4-pregnadiene-3, 20-diketone

Abstract

The invention provides a purification method of 11 beta, 17 alpha-dyhydroxyl-6-methyl-1, 4-pregnadiene-3, 20-diketone, and relates to the technical field of medicine purification, in particular to a purification method of 11 beta, 17 alpha-dyhydroxyl-6-methyl-1, 4-pregnadiene-3, 20-diketone. The method comprises the steps of biotransformation and two-time purification, in the first-time purification, purification of a Girard reagent and secondary purification of an alcohol solvent are combined, and in the second-time purification, the alcohol solvent is adopted for further treatment. The purification method provided by the invention effectively solves the problem that the traditional method has a poor purification effect on the raw material 11beta, 17alpha-dihydroxy-6-methyl-progesterone, the purity of the product treated by the method is as high as 98.5%, the content of the incompletely reacted raw material is less than 1%, the content of single impurity is less than 0.3%, and the purification yield is as high as 80%. Meanwhile, the purification method provided by the invention is simple to operate, mild in condition, relatively low in equipment requirement, short in treatment period, high in cost benefit and easy for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug purification, and particularly to a purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione. Background Art

[0002] Methylprednisolone, as an important adrenocortical hormone drug, is widely recognized for its excellent drug activity. Clinically, it is mainly used to treat various inflammatory and immune system-related diseases, and has significant preventive and therapeutic effects on secondary spinal cord injuries. In addition, methylprednisolone has an anti-inflammatory activity 7 times stronger than that of cortisone, and can effectively improve the microenvironment near the nerve injury site, which makes it one of the important choices for dealing with the acute phase of nerve injury. Its mechanism of action is not limited to anti-inflammation, but also includes the impact on cell metabolism, thus helping to reduce tissue edema, stabilize lysosomal membranes and reduce the release of harmful substances.

[0003] 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione is an important precursor for the synthesis of methylprednisolone, and methylprednisolone can be obtained through iodination hydrolysis. However, in the actual production process, this conversion step faces a major challenge: the polarity between the dehydrogenation product and the starting material is very close, which makes it difficult to separate the two, thereby affecting the purity of the final product. This similarity increases the difficulty in the purification process, and traditional physical methods such as crystallization or extraction with simple solvents often cannot effectively remove these impurities.

[0004] In view of the above problems, researchers have explored various strategies to improve the purity of methylprednisolone. On the one hand, improving the chemical synthesis route, such as adjusting the reaction conditions or introducing new reagents, can reduce the formation of by-products to a certain extent, thus simplifying the subsequent purification process. For example, optimizing the temperature, concentration, and catalyst selection in the iodide hydrolysis step can effectively reduce the formation of by-products such as dehydrogenated products, thereby reducing the subsequent separation difficulty. However, although this method can reduce impurities at the source, it may require a large number of experiments to find the optimal conditions, and in some cases, it may increase the raw material cost or generate more waste. On the other hand, adopting advanced separation technologies, such as high-performance liquid chromatography (HPLC) or supercritical fluid extraction (SFE), can more precisely separate the target compound from complex mixtures. However, this treatment is accompanied by high equipment investment and operating costs, and the operation complexity is high, requiring high professional skills of technicians. For another example: The existing patent CN1089121192A uses the enzyme conversion solution obtained by the biotransformation reaction of 11β,17α-dihydroxy-6-methylprogesterone to purify 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione. This process is cumbersome and has a large solvent consumption, and there are still problems such as poor purification effect on 11β,17α-dihydroxy-6-methylprogesterone.

[0005] Therefore, considering factors such as the pollution of the purification process to the surrounding environment, purification cost, and operation difficulty, it is urgent to develop a new purification method for 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione. Summary of the Invention

[0006] In view of this, the present invention provides a method for 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione with simple operation, environmental protection, high purification yield, and high purity.

[0007] The present invention provides a purification method for 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione, comprising the following steps:

[0008] Step 1: Perform a biotransformation reaction on 11β,17α-dihydroxy-6-methylprogesterone by dehydrogenase to obtain an enzyme conversion solution;

[0009] Step 2: Add diatomaceous earth to the enzyme conversion solution obtained in Step 1, heat and stir, and perform suction filtration to obtain an aqueous phase and a solid mycelium phase; extract the aqueous phase and the solid mycelium phase respectively with ethyl acetate, mix the ethyl acetate obtained after the two extractions, and concentrate under reduced pressure to obtain a crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione;

[0010] Step 3: Dissolve the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione obtained in Step 2 in an alcohol solvent, heat to reflux, then add Girard reagent and glacial acetic acid, stir, concentrate under reduced pressure, add water and continue to stir, and filter by suction to obtain the purified product I;

[0011] Step 4: Mix the purified product I obtained in Step 3 with an alcohol solvent, heat to reflux, cool down to crystallize, and filter by suction to obtain purified 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione.

[0012] On the basis of the above technical solution, preferably, in Step 2, the amount of the diatomaceous earth is 3 to 4 times that of the enzyme conversion solution, and the temperature of the heating and stirring is 50 to 60 °C.

[0013] On the basis of the above technical solution, preferably, in Step 2, the mass ratio of ethyl acetate to the aqueous phase is 50:1; the mass ratio of ethyl acetate to the solid mycelium phase is 50:1; the temperature of the heating and refluxing is 75 to 80 °C, and the time is 20 to 40 min; the temperature of the concentration under reduced pressure is 35 to 40 °C, and the vacuum degree is -0.08 MPa to -0.10 MPa.

[0014] On the basis of the above technical solution, preferably, in Step 3, the alcohol solvent is methanol, and the mass ratio of methanol to the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione is 30:1.

[0015] On the basis of the above technical solution, preferably, in Step 3, the mass ratio of Girard reagent to the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione is (0.085 - 0.19):1; the temperature of the heating and refluxing is 60 to 70 °C, and the time is 20 to 30 min; the temperature of the concentration under reduced pressure is 35 to 40 °C, and the vacuum degree is -0.08 MPa to -0.10 MPa.

[0016] On the basis of the above technical solution, preferably, in Step 3, the mass ratio of water to the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione is (8 - 12):1.

[0017] On the basis of the above technical solution, preferably, in Step 4, the alcohol solvent is selected from methanol with a mass percentage concentration of 80 to 100%.

[0018] Based on the above technical solutions, preferably, the temperature for heating and refluxing is 60 - 70 °C, and the time is 20 - 30 min; the crystallization temperature is 0 - 5 °C.

[0019] The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione provided by the present invention has the following beneficial effects compared with the prior art:

[0020] (1) The purification method provided by the present invention effectively solves the problem of poor purification effect of the traditional method on the raw material 11β,17α-dihydroxy-6-methyl progesterone. At the same time, the purification method described in the present invention is not only simple in operation, mild in conditions, but also has low requirements for equipment, short processing cycle, high cost-effectiveness, and is easy to be mass-produced industrially.

[0021] (2) For the product after purification treatment by the present invention, its purity is as high as 98.5%, the content of unreacted raw materials is less than 1%, the single impurity is less than 0.3%, and the purification yield is as high as 80%. Detailed implementation manners

[0022] Next, in combination with the implementation manners of the present invention, the technical solutions in the implementation manners of the present invention will be described clearly and completely. Obviously, the described implementation manners are only a part of the implementation manners of the present invention, rather than all of the implementation manners. Based on the implementation manners in the present invention, all other implementation manners obtained by those of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

[0023] It should be noted that in this article, the term "concentration under reduced pressure" (also known as vacuum distillation) is an important method for separating and purifying compounds, especially suitable for the separation and purification of high-boiling substances and those compounds that decompose, oxidize, or polymerize before reaching the boiling point during atmospheric distillation.

[0024] The following is a further description of the present invention in combination with specific examples. The protection scope of the present invention is not limited by the following examples. The sources of the main materials involved in the examples are shown in Table 1 below, and the remaining materials not shown are all conventional commercially available products.

[0025] Table 1 Description of material sources

[0026] Serial Number Material / Equipment Name Specification / Model Manufacturer 1 Girard`s Reagent T Purity 98%, 18227E Adamas 2 Acetic Acid DG73562B Exploration Platform Greagent 3 Ethyl Acetate G23272P Exploration Platform Greagent 4 Methanol G75851AD Exploration Platform Greagent 5 Isopropyl Alcohol G75885B Exploration Platform Greagent 6 tert-Butyl Alcohol G81329F Exploration Platform Greagent 7 Ethanol G73537C Exploration Platform Greagent 8 11β,17α-Dihydroxy-6-methyl-progesterone AC000801020 Exploration Platform Greagent

[0027] It should be noted that in the present invention, the biotransformation reactions involved in the steps of the examples are all carried out with reference to the invention patent CN118581187A of Hubei Gongtong Steroid Pharmaceutical Research Institute Co., Ltd., and will not be further described in the specific examples.

[0028] The following are the specific examples of the present invention.

[0029] Example 1

[0030] The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione in this example includes the following steps:

[0031] Step 1: Take 20 g of 11β,17α-dihydroxy-6-methyl progesterone for biotransformation reaction to obtain an enzyme conversion solution;

[0032] Step 2: Take 700 ml of the enzyme conversion solution from Step 1, add 60 g of diatomaceous earth thereto, heat and stir at 60 °C for 30 min, and perform suction filtration to obtain an aqueous phase and a solid mycelium phase; extract the solid mycelium phase with 1000 ml of ethyl acetate, heat and reflux at 78 °C for 1 h, then perform suction filtration to obtain organic phase I; take another 1000 ml of ethyl acetate to extract the aqueous phase, extract at 30 °C for 30 min, then let it stand for layering to obtain organic phase II; mix organic phase I and organic phase II, and perform vacuum concentration at a vacuum degree of -0.08 MPa and 38 °C to obtain a yellow solid, that is, 20.8 g of crude 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione;

[0033] Step 3: Dissolve 20.8 g of the crude 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione prepared in Step 2 in 600 g of methanol, reflux and dissolve until clear at 65 °C, then add 3.0 g of Girard reagent and 1.0 ml of glacial acetic acid, stir for 1 h, perform vacuum concentration at 38 °C, add 200 g of water and stir at room temperature, and perform suction filtration to obtain 19.53 g of slightly yellow solid purified product I;

[0034] Step 4: Mix the purified product I from Step 3 with 195 g of methanol, reflux and dissolve until clear at 65 °C, cool to 0 °C for crystallization and suction filtration, and dry at 60 °C to obtain 15.88 g of purified white solid 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione.

[0035] Example 2

[0036] The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione in this example includes the following steps:

[0037] Step 1: Take 20 g of 11β,17α-dihydroxy-6-methyl progesterone for biotransformation reaction to obtain an enzyme conversion solution;

[0038] Step 2: Take 700 ml of the enzyme conversion solution from Step 1, add 60 g of diatomaceous earth thereto, heat and stir at 60 °C for 30 min, then perform suction filtration to obtain an aqueous phase and a solid mycelium phase; extract the solid mycelium phase with 1000 ml of ethyl acetate, heat and reflux at 78 °C for 1 h, then perform suction filtration to obtain organic phase I; separately take 1000 ml of ethyl acetate to extract the aqueous phase, extract at 30 °C for 30 min, then let it stand for layering to obtain organic phase II; mix organic phase I and organic phase II, and perform vacuum concentration at a vacuum degree of -0.08 MPa and 38 °C to obtain a yellow solid, namely 18.4 g of the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione;

[0039] Step 3: Dissolve 18.4 g of the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione prepared in Step 2 in 600 g of methanol, reflux and dissolve until clear at 65 °C, then add 3.8 g of Girard reagent and 1.2 ml of glacial acetic acid, stir for 1 h, perform vacuum concentration at 38 °C, then add 200 g of water and stir at room temperature, and perform suction filtration to obtain 17.21 g of a slightly yellow solid purified product I;

[0040] Step 4: Mix the purified product I from Step 3 with 172 g of methanol, reflux and dissolve until clear at 65 °C, cool to 0 °C for crystallization and suction filtration, and dry at 60 °C to obtain 14.26 g of purified white solid 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione.

[0041] Example 3

[0042] The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione in this example includes the following steps:

[0043] Step 1: Take 16 g of 11β,17α-dihydroxy-6-methyl progesterone for biotransformation reaction to obtain an enzyme conversion solution;

[0044] Step 2: Take 700 ml of the enzyme conversion solution from Step 1, add 60 g of diatomaceous earth thereto, heat and stir at 60 °C for 30 min, then perform suction filtration to obtain an aqueous phase and a solid mycelium phase; extract the solid mycelium phase with 1000 ml of ethyl acetate, heat and reflux at 78 °C for 1 h, then perform suction filtration to obtain organic phase I; separately take 1000 ml of ethyl acetate to extract the aqueous phase, extract at 30 °C for 30 min, then let it stand for layering to obtain organic phase II; mix organic phase I and organic phase II, and perform vacuum concentration at a vacuum degree of -0.08 MPa and 38 °C to obtain a yellow solid, namely 16.2 g of the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione;

[0045] Step 3: Dissolve 16.2 g of the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione prepared in Step 2 in 600 g of methanol. After refluxing and dissolving clearly at 65°C, add 1.7 g of Girard's reagent and 0.6 ml of glacial acetic acid. After stirring for 1 h, concentrate under reduced pressure at 38°C, then add 200 g of water and stir at room temperature. Filter by suction to obtain 15.3 g of a slightly yellow solid purified product I;

[0046] Step 4: Mix the purified product I from Step 3 with 150 g of methanol, reflux and dissolve clearly at 65°C, cool to 0°C for crystallization and suction filtration, and dry at 60°C to obtain 11.88 g of purified white solid 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione.

[0047] Comparative Example 1

[0048] The difference from Example 1 is that in Step 3, the methanol ratio is replaced from 30 times to 10 times, and the other steps are the same.

[0049] Comparative Example 2

[0050] The difference from Example 1 is that in Step 3, the methanol ratio is replaced from 30 times to 50 times, and the other steps are the same.

[0051] Comparative Example 3

[0052] The difference from Example 1 is that in Step 4, methanol is replaced with isopropanol, and the other steps are the same.

[0053] Comparative Example 4

[0054] The difference from Example 1 is that in Step 4, methanol is replaced with tert-butanol, and the other steps are the same.

[0055] Comparative Example 5

[0056] The difference from Example 1 is that in Step 3, the dosage of Girard's reagent is replaced from 0.15 times to 0.06 times, and the other steps are the same.

[0057] Comparative Example 6

[0058] The difference from Example 1 is that in Step 4, methanol is replaced with acetone, and the other steps are the same.

[0059] Comparative Example 7

[0060] The difference from Example 1 is that in Step 4, methanol is replaced with N,N-dimethylformamide, and at the same time the solvent amount is reduced to 5 times the amount of the purified product I, and the other steps are the same.

[0061] Comparative Example 8

[0062] The purification method of this comparative example includes the following steps:

[0063] Step 1: Take 20 g of 11β,17α-dihydroxy-6-methyl-progesterone for biotransformation reaction to obtain an enzyme conversion solution;

[0064] Step 2: Take 700 ml of the enzyme conversion solution from Step 1, add 60 g of diatomaceous earth thereto, heat and stir at 60 °C for 30 min, filter by suction to obtain an aqueous phase and a solid mycelium phase; extract the solid mycelium phase with 1000 ml of ethyl acetate, heat under reflux at 78 °C for 1 h, then filter by suction to obtain organic phase I; take another 1000 ml of ethyl acetate to extract the aqueous phase, heat under reflux at 78 °C for 1 h, then filter by suction to obtain organic phase II; mix organic phase I and organic phase II, and concentrate under reduced pressure under the conditions of a vacuum degree of -0.08 MPa and 38 °C to obtain a yellow solid, namely 20.12 g of crude 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione;

[0065] Step 3: Dissolve 20.12 g of the crude 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione prepared in Step 2 in 200 g of methanol, reflux and dissolve until clear at 65 °C, then cool to 0 °C for crystallization, filter by suction, and dry to obtain 15.2 g of a white solid purified product I;

[0066] Step 4: Mix the purified product I from Step 3 with 152 g of methanol, reflux and dissolve until clear at 65 °C, then cool to 0 °C for crystallization, filter by suction, and dry to obtain 13.66 g of purified white solid 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione.

[0067] Comparative Example 9

[0068] The purification method of this comparative example includes the following steps:

[0069] Step 1: Take 20 g of 11β,17α-dihydroxy-6-methyl-progesterone for biotransformation reaction to obtain an enzyme conversion solution;

[0070] Step 2: Take 700 ml of the enzyme conversion solution from Step 1, add 60 g of diatomaceous earth thereto, heat and stir at 60 °C for 30 min, and perform suction filtration to obtain an aqueous phase and a solid mycelium phase; extract the solid mycelium phase with 1000 ml of ethyl acetate, heat and reflux at 78 °C for 1 h, and then perform suction filtration to obtain organic phase I; take another 1000 ml of ethyl acetate to extract the aqueous phase, heat and reflux at 78 °C for 1 h, and then perform suction filtration to obtain organic phase II; mix organic phase I and organic phase II, and concentrate under reduced pressure under the conditions of a vacuum degree of -0.08 MPa and 38 °C to obtain a yellow solid, namely 20.12 g of the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione;

[0071] Step 3: Dissolve 20.12 g of the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione prepared in Step 2 in 200 g of methanol, reflux and dissolve until clear at 65 °C, then cool to 0 °C for crystallization, suction filtration, and drying to obtain 15.2 g of a purified white solid product I;

[0072] Step 4: Mix the purified product I from Step 3 with 300 g of methanol, reflux and dissolve until clear at 65 °C, cool to 0 °C for crystallization, suction filtration, and drying to obtain 13.27 g of the purified white solid 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione.

[0073] Comparative Example 10

[0074] The difference from Example 1 is that Step 4 is set to repeat the operation of Step 3, and the remaining steps remain unchanged.

[0075] The inventor used the HPLC method to analyze the components of the white solids obtained in Examples 1 to 7 and Comparative Examples 1 to 6 above, and the results are shown in Table 2:

[0076] Table 2 Component Analysis Table

[0077]

[0078]

[0079] It can be seen from Experimental Example 1 and Comparative Examples 1 to 2 that if the amount of solvent is insufficient during the purification with Girard reagent, the purity will decrease, and the single impurity of the product will be higher than 0.15%. If an excessive amount of solvent is added, the reaction concentration will be too low, resulting in a poor raw material removal effect. At the same time, it can be seen from Comparative Example 5 that if the amount of Girard reagent is reduced during the purification with Girard reagent, the raw material removal effect will also be poor.

[0080] It can be seen from Experimental Example 1, Comparative Examples 3-4 and Comparative Examples 8-9 that the purification effect is better after the combination of Girard reagent purification and diol alcohol solvent. This is both because the partition ratio of its raw materials and products in the alcohol solvent is smaller, and also because the polarity of this kind of substance is relatively large among steroids, which ultimately makes the combination purification of alcohol solvent and Girard reagent have a better effect.

[0081] It can be seen from Experimental Example 1 and Comparative Examples 6-7 that the use of Girard reagent for purification can well improve the removal rate of impurities, reduce the monohydric alcohol mother liquor at the same time, and ultimately increase the purification yield by 12%. The method of Example 1 has obvious advantages.

[0082] It can be seen from Example 1 and Comparative Example 10 that continuing to use Girard reagent for purification can increase the yield, but it will lead to a decrease in purity, and the raw material exceeds 1%. The reason may be analyzed as follows: Since the reaction activities of the product and the raw material with Girard reagent after dissolution are different, more raw materials can combine with Girard to form hydrazone substances and dissolve in water, thus having a certain purification effect. However, when the purity of the raw material is reduced to a certain extent, the contact reaction probability between the product in the solvent system and Girard reagent becomes larger, and the purification effect decreases, and finally qualified products cannot be obtained.

[0083] The above is only the preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione, characterized in that, It includes the following steps: Step 1: Perform a biotransformation reaction on 11β,17α-dihydroxy-6-methyl-progesterone with dehydrogenase to obtain an enzyme conversion solution. Step 2: Add diatomaceous earth to the enzyme conversion solution obtained in Step 1, heat and stir, then perform suction filtration to obtain an aqueous phase and a solid mycelium phase; use ethyl acetate to extract the aqueous phase and the solid mycelium phase respectively, mix the ethyl acetate obtained from the two extractions and concentrate under reduced pressure to obtain a crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione. Step 3: Dissolve the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione obtained in Step 2 in an alcohol solvent, heat under reflux, then add Girard reagent and glacial acetic acid, stir, concentrate under reduced pressure, add water and continue to stir, then perform suction filtration to obtain purified product I. Step 4: Mix the purified product I obtained in Step 3 with an alcohol solvent, heat under reflux, cool to crystallize and perform suction filtration to obtain purified 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione.

2. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione as claimed in claim 1, characterized in that, In Step 2, the amount of the diatomaceous earth is 3 to 4 times that of the enzyme conversion solution, and the temperature of the heating and stirring is 50 to 60 °C.

3. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione as described in claim 2, characterized in that, In Step 2, the mass ratio of ethyl acetate to the aqueous phase is 50:1 for the aqueous phase; the mass ratio of ethyl acetate to the solid mycelium phase is 50:1 for the solid mycelium phase. The temperature of the heating under reflux is 75 to 80 °C, and the time is 20 to 40 min. The temperature of the concentration under reduced pressure is 35 to 40 °C, and the vacuum degree is -0.08 MPa to -0.10 MPa.

4. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione as described in claim 1, characterized in that, In Step 3, the alcohol solvent is methanol, and the mass ratio of methanol to the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione is 30:

1.

5. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione as described in claim 4, characterized in that, In Step 3, the mass ratio of Girard reagent to the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione is (0.085 - 0.19):

1. The temperature of the heating under reflux is 60 to 70 °C, and the time is 20 to 30 min. The temperature of the concentration under reduced pressure is 35 to 40 °C, and the vacuum degree is -0.08 MPa to -0.10 MPa.

6. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione as claimed in claim 5, characterized in that, In Step 3, the mass ratio of water to the crude product of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione is (8 - 12):

1.

7. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione as claimed in claim 1, characterized in that, In Step 4, the alcohol solvent is selected from methanol with a mass percentage concentration of 80 to 100%.

8. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione as claimed in claim 7, characterized in that, The mass ratio of methanol to the purified product I is (10 - 20):

1.

9. The purification method of 11β,17α-dihydroxy-6-methyl-1,4-pregnadiene-3,20-dione according to claim 7, characterized in that, The temperature of the heating under reflux is 60 to 70 °C, and the time is 20 to 30 min; the crystallization temperature is 0 to 5 °C.

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