Preparation method of methylprednisolone

Abstract

The invention provides a preparation method of methylprednisolone, and belongs to the technical field of chemical synthesis. In the methylene hydrogenation process, hydrogen, ammonium formate, boric acid or formic acid is used as a hydrogen donor, so that the use of cyclohexene can be avoided, and the preparation process is more environment-friendly; 2, 3-dichloro-5, 6-dicyanobenzoquinone is adopted as an oxidizing agent, selective dehydrogenation is performed under the action of a specific type of catalyst 4, high-purity 1, 2 dehydrogenated substances are prepared with high yield, and then the yield and purity of subsequent reaction products are guaranteed; according to the method, methylprednisolone is taken as a raw material, then selective reduction is directly carried out at a certain temperature under catalysis of a catalyst, a methylprednisolone acetate crude product is prepared with high yield, finally, methylprednisolone is prepared with high yield through adsorption purification and purification after hydrolysis, and meanwhile, the purity is improved. The methylprednisolone prepared by the preparation method provided by the invention has a total yield of 59.6% or more and a purity of 99.5% or more, and has high yield and high purity.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of methylprednisolone. Background Art

[0002] Methylprednisolone, also known as methylprednisone and Solu-Medrol, has the chemical name of 16α-methyl-11β,17α,21-trihydroxy-6α-methylpregna-1,4-diene-3,20-dione. It is a glucocorticoid developed by the Upjohn Company in the late 1950s. Due to its powerful anti-inflammatory, immunosuppressive, anti-allergic, anti-shock and other pharmacological effects, it is widely used clinically in respiratory diseases, endocrine disorders, rheumatic diseases, collagen diseases, blood diseases, skin diseases, allergic conditions, nervous system diseases, gastrointestinal diseases, organ transplantation, etc. Compared with prednisone, it has the characteristics of rapid onset, strong anti-inflammatory effect, short half-life, weak mineralocorticoid-like effect and weak impact on adrenal cortical function, and has a good therapeutic effect / price ratio, being an updated alternative product to prednisone.

[0003] The preparation process of methylprednisolone usually adopts the semi-synthetic method, selecting a suitable steroid compound as the starting material and obtaining the target product through a series of reactions. There are many synthetic process routes for methylprednisolone, among which 6-position methylation, 1,2-position dehydrogenation process and 21-position hydroxylation are the key steps in the production process of methylprednisolone, directly affecting its production cost and quality.

[0004] In related research, taking cortisone acetate as the raw material, first introducing a methylene group at the 6-position through enol etherification and Mannich reaction, then hydrogenating with cyclohexene and generating the 6α-methyl compound through configuration conversion, then dehydrogenating at the 1,2-position by biological method, protecting the 3,20-position carbonyl with ethylene glycol acetal, and reducing the 11-position carbonyl to obtain methylprednisolone. This method uses cyclohexene as the hydrogen donor, which has great toxicity and irritation, and the total yield of methylprednisolone is only 36.7%, and the purity is only 97.8%. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method of methylprednisolone. The preparation method provided by the present invention is more environmentally friendly, and the prepared methylprednisolone has a high yield and high purity.

[0006] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0007] The present invention provides a preparation method of methylprednisolone, comprising the following steps:

[0008] (1) Mix cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 for an etherification reaction, then add organic secondary amine and aldehyde for a Mannich reaction, and then add acid for a decomposition reaction to obtain a methylene compound;

[0009] (2) Mix the methylene compound obtained in step (1), solvent 2, catalyst 2, catalyst 3 and hydrogen donor for a hydrogenation reaction to obtain a 6a-methyl compound; the hydrogen donor is hydrogen, ammonium formate, boric acid or formic acid;

[0010] (3) Mix the 6a-methyl compound obtained in step (2), solvent 3, catalyst 4 and oxidant for an oxidation reaction to obtain a 1,2-dehydrogenated compound; the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone; the catalyst 4 is trifluoroacetic acid, N,O-bis(trimethylsilyl)acetamide or trimethylchlorosilane;

[0011] (4) Mix the 1,2-dehydrogenated compound obtained in step (3), solvent 4, catalyst 5 and reducing agent for a reduction reaction to obtain crude methylprednisolone acetate; the catalyst 5 is calcium chloride, magnesium chloride, zinc chloride or barium chloride; the temperature of the reduction reaction is -40 to -30 °C;

[0012] (5) Mix the crude methylprednisolone acetate obtained in step (4), solvent 4 and adsorbent for adsorption, and then perform crystallization and recrystallization in sequence to obtain high-quality methylprednisolone acetate;

[0013] (6) Mix the high-quality methylprednisolone acetate obtained in step (5), solvent 5 and alkali solution for a hydrolysis reaction to obtain crude methylprednisolone;

[0014] (7) Mix the crude methylprednisolone obtained in step (6), solvent 5 and adsorbent for adsorption and then crystallization to obtain methylprednisolone.

[0015] Preferably, the mass ratio of cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 in step (1) is 1:(3 - 20):(0.1 - 1):(0.5 - 1):(0.001 - 0.005);

[0016] The molar ratio of cortisone acetate, organic secondary amine and aldehyde is 1:(1 - 2):(1 - 2);

[0017] The solvent 1 is methanol, ethanol, tetrahydrofuran or acetic acid;

[0018] The etherifying agent is methanol or ethanol;

[0019] The dehydrating agent is triethyl orthoformate, trimethyl orthoformate, trimethyl orthoacetate or triethyl orthoacetate;

[0020] The catalyst 1 is sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or methanesulfonic acid;

[0021] The organic secondary amine is dimethylamine, diethylamine, N-methylaniline or piperidine;

[0022] The aldehyde is formaldehyde, trioxymethylene or paraformaldehyde.

[0023] Preferably, in the step (2), the mass ratio of the methylene compound, the solvent 2 and the catalyst 2 is 1:(3-10):(0.02-0.1);

[0024] The molar ratio of the methylene compound, the catalyst 3 and the hydrogen donor is 1:(0.01-0.05):(1-2);

[0025] The solvent 2 is a mixed solvent of solvent A and solvent B; the solvent A is dichloromethane or chloroform; the solvent B is tetrahydrofuran, methanol, ethanol or acetonitrile;

[0026] The catalyst 2 is palladium on carbon with a palladium mass percentage of 3-10%, PtO 2 or Pd(OAc) 2 ;

[0027] The catalyst 3 is p-toluenesulfonic acid, sulfuric acid, perchloric acid or methanesulfonic acid.

[0028] Preferably, in the step (2), the temperature of the hydrogenation reaction is 5-35°C.

[0029] Preferably, in the step (3), the mass ratio of the 6a-methyl compound and the solvent 3 is 1:(5-20);

[0030] The molar ratio of the 6a-methyl compound, the catalyst 4 and the oxidant is 1:(0.01-0.05):(1-1.5);

[0031] The solvent 3 is tetrahydrofuran, ethyl acetate, toluene, dioxane or methylcyclohexane.

[0032] Preferably, in the step (3), the temperature of the oxidation reaction is 0-65°C.

[0033] Preferably, in the step (4), the mass ratio of the 1,2-dehydro compound and the solvent 4 is 1:(5-20);

[0034] The molar ratio of the 1,2-dehydro compound, the catalyst 5 and the reducing agent is 1:(0.1-0.5):(1-2);

[0035] The solvent 4 is a mixed solvent of solvent A and solvent C; the solvent A is dichloromethane or chloroform; the solvent C is methanol or ethanol;

[0036] The reducing agent is potassium borohydride or sodium borohydride.

[0037] Preferably, in the step (5), the adsorbent is activated carbon or neutral alumina;

[0038] The mass ratio of the crude methylprednisolone acetate to the activated carbon is 1:(0.01 - 0.05);

[0039] The mass ratio of the crude methylprednisolone acetate to the neutral alumina is 1:(0.1 - 0.5).

[0040] Preferably, in the step (6), the mass ratio of the refined methylprednisolone acetate to the solvent 5 is 1:(5 - 20); the mass ratio of the refined methylprednisolone acetate to the alkali solution is 1:(0.5 - 2);

[0041] The solvent 5 is a mixed solvent of solvent A and solvent C; the solvent A is dichloromethane or chloroform; the solvent C is methanol or ethanol;

[0042] The alkali solution is a mixed solution of solution D and solution E; the solution D is a methanol / ethanol solution of sodium hydroxide / potassium hydroxide; the solution E is an aqueous solution of potassium carbonate / sodium carbonate;

[0043] The concentration of the solution D is 0.05wt%; the concentration of the solution E is 0.01wt%.

[0044] Preferably, in the step (6), the temperature of the hydrolysis reaction is -20 to 0°C.

[0045] The present invention provides a method for preparing methylprednisolone, comprising the following steps: (1) Mixing cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 for etherification reaction, then adding organic secondary amine and aldehyde for Mannich reaction, and then adding acid for decomposition reaction to obtain methylene compound; (2) Mixing the methylene compound obtained in step (1), solvent 2, catalyst 2, catalyst 3 and hydrogen donor for hydrogenation reaction to obtain 6a-methyl compound; the hydrogen donor is hydrogen, ammonium formate, boric acid or formic acid; (3) Mixing the 6a-methyl compound obtained in step (2), solvent 3, catalyst 4 and oxidizing agent for oxidation reaction to obtain 1,2-dehydro compound; the oxidizing agent is 2,3-dichloro-5,6-dicyanobenzoquinone; the catalyst 4 is trifluoroacetic acid, N,O-bis(trimethylsilyl)acetamide or trimethylchlorosilane; (4) Mixing the 1,2-dehydro compound obtained in step (3), solvent 4, catalyst 5 and reducing agent for reduction reaction to obtain crude methylprednisolone acetate; the catalyst 5 is calcium chloride, magnesium chloride, zinc chloride or barium chloride; the temperature of the reduction reaction is -40 to -30 °C; (5) Mixing the crude methylprednisolone acetate obtained in step (4), solvent 4 and adsorbent for adsorption, followed by crystallization and recrystallization to obtain high-quality methylprednisolone acetate; (6) Mixing the high-quality methylprednisolone acetate obtained in step (5), solvent 5 and alkaline solution for hydrolysis reaction, followed by crystallization to obtain crude methylprednisolone; (7) Mixing the crude methylprednisolone obtained in step (6), solvent 5 and adsorbent for adsorption, followed by crystallization to obtain methylprednisolone. In the present invention, hydrogen, ammonium formate, boric acid or formic acid is used as the hydrogen donor during the hydrogenation of the methylene compound, which can avoid the use of cyclohexene and make the preparation process more environmentally friendly; then 2,3-dichloro-5,6-dicyanobenzoquinone is used as the oxidizing agent, and selective dehydrogenation is carried out under the action of a specific type of catalyst 4 to prepare 1,2-dehydro compound with high purity in high yield, thereby ensuring the yield and purity of the subsequent reaction products; then selective reduction is directly carried out under the catalysis of a certain temperature and catalyst to prepare crude methylprednisolone acetate in high yield, and finally high-quality methylprednisolone is prepared in high yield through adsorption purification and purification after hydrolysis, while improving the purity. The results of the examples show that the total yield of methylprednisolone prepared by the preparation method provided by the present invention is above 59.6%, and the purity is above 99.5%, with high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 It is the liquid chromatogram of the methylprednisolone prepared in Example 1 of the present invention;

[0047] Figure 2 It is the liquid chromatogram of the methylprednisolone prepared in Example 2 of the present invention;

[0048] Figure 3It is the liquid chromatogram of methylprednisolone prepared in Example 3 of the present invention;

[0049] Figure 4 It is the liquid chromatogram of methylprednisolone prepared in Example 4 of the present invention;

[0050] Figure 5 It is the liquid chromatogram of methylprednisolone prepared in Example 5 of the present invention. Detailed implementation manners

[0051] The present invention provides a preparation method of methylprednisolone, comprising the following steps:

[0052] (1) Mix cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 for etherification reaction, then add organic secondary amine and aldehyde for Mannich reaction, and then add acid for decomposition reaction to obtain methylene compound;

[0053] (2) Mix the methylene compound obtained in the step (1), solvent 2, catalyst 2, catalyst 3 and hydrogen donor for hydrogenation reaction to obtain 6a-methyl compound; the hydrogen donor is hydrogen, ammonium formate, boric acid or formic acid;

[0054] (3) Mix the 6a-methyl compound obtained in the step (2), solvent 3, catalyst 4 and oxidant for oxidation reaction to obtain 1,2-dehydrogenated compound; the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone; the catalyst 4 is trifluoroacetic acid, N,O-bis(trimethylsilyl)acetamide or trimethylchlorosilane;

[0055] (4) Mix the 1,2-dehydrogenated compound obtained in the step (3), solvent 4, catalyst 5 and reducing agent for reduction reaction to obtain crude methylprednisolone acetate; the catalyst 5 is calcium chloride, magnesium chloride, zinc chloride or barium chloride; the temperature of the reduction reaction is -40 to -30 °C;

[0056] (5) Mix the crude methylprednisolone acetate obtained in the step (4), solvent 4 and adsorbent for adsorption, and then perform crystallization and recrystallization in sequence to obtain high-quality methylprednisolone acetate;

[0057] (6) Mix the high-quality methylprednisolone acetate obtained in the step (5), solvent 5 and alkali solution for hydrolysis reaction, and then perform crystallization to obtain crude methylprednisolone;

[0058] (7) Mix the crude methylprednisolone obtained in the step (6), solvent 5 and adsorbent for adsorption, and then perform crystallization to obtain methylprednisolone.

[0059] In the present invention, cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 are mixed for an etherification reaction, then an organic secondary amine and an aldehyde are added for a Mannich reaction, and then an acid is added for a decomposition reaction to obtain a methylene compound.

[0060] As an embodiment of the present invention, the solvent 1 can be methanol, ethanol, tetrahydrofuran or acetic acid; the etherifying agent can be methanol or ethanol; the dehydrating agent can be triethyl orthoformate, trimethyl orthoformate, trimethyl orthoacetate or triethyl orthoacetate; the catalyst 1 can be sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or methanesulfonic acid. Using sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or methanesulfonic acid as the catalyst in the present invention is more conducive to the progress of the etherification reaction.

[0061] As an embodiment of the present invention, the mass ratio of cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 can be 1:(3 - 20):(0.1 - 1):(0.5 - 1):(0.001 - 0.005), can also be 1:(5 - 18):(0.3 - 0.8):(0.6 - 0.9):(0.002 - 0.004), and can also be 1:(10 - 15):(0.5 - 0.8):(0.8 - 0.9):(0.003 - 0.004). Limiting the mass ratio of cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 within the above range in the present invention can result in a product with better quality after the etherification reaction.

[0062] As an embodiment of the present invention, the etherification reaction can be carried out under stirring; the temperature of the etherification reaction can be 20 - 40 °C, can also be 25 - 35 °C, and can also be 30 °C. There is no special limitation on the time of the etherification reaction in the present invention, and it can be stopped after detecting the end of the reaction by thin layer chromatography (TLC detection). Limiting the temperature of the etherification reaction within the above range in the present invention can ensure the smooth progress of the etherification reaction.

[0063] In the present invention, the chemical changes occurring during the etherification reaction are shown in Formula 1:

[0064]

[0065] As an embodiment of the present invention, the organic secondary amine can be dimethylamine, diethylamine, N-methylaniline or piperidine; the aldehyde can be formaldehyde, trioxane or paraformaldehyde. Limiting the types of organic secondary amine and aldehyde within the above range in the present invention is more conducive to the progress of the Mannich reaction.

[0066] As an embodiment of the present invention, the formaldehyde can be used in the form of an aqueous solution; the concentration of the formaldehyde aqueous solution can be 30 - 37 wt%.

[0067] As an embodiment of the present invention, the molar ratio of cortisone acetate, organic secondary amine and aldehyde can be 1:(1-2):(1-2), can also be 1:(1.2-1.8):(1.2-1.8), and can also be 1:(1.4-1.6):(1.4-1.6). Limiting the molar ratio of cortisone acetate, organic secondary amine and aldehyde within the above range in the present invention can result in a product with better quality after the Mannich reaction.

[0068] As an embodiment of the present invention, the temperature of the Mannich reaction can be 20-40°C, can also be 25-35°C, and can also be 30°C. The present invention has no special limitation on the time of the Mannich reaction, and it can be stopped after detecting the end of the reaction by thin layer chromatography (TLC). Limiting the temperature of the Mannich reaction within the above range in the present invention can ensure the smooth progress of the Mannich reaction.

[0069] In the present invention, the chemical changes occurring during the Mannich reaction are shown in Formula 2:

[0070]

[0071] As an embodiment of the present invention, the acid can be hydrochloric acid or sulfuric acid; the concentration of the hydrochloric acid can be 18-36 wt%; the concentration of the sulfuric acid can be 20-50 wt%. The present invention has no special limitation on the addition amount of the acid, and it is only necessary to adjust the pH of the mixed solution to 2. Adjusting the pH value of the mixed solution to 2 in the present invention can promote the decomposition reaction.

[0072] In the present invention, the chemical changes occurring during the decomposition reaction are shown in Formula 3:

[0073]

[0074] As an embodiment of the present invention, after adding the acid, it further includes negative pressure concentration; the negative pressure of the negative pressure concentration can be -0.09 to -0.06 MPa. The present invention can evaporate the solvent in the reaction solution through negative pressure concentration.

[0075] After negative pressure concentration, the present invention preferably adds water to the product obtained by negative pressure concentration, stirs it, and then filters, washes and dries it in sequence to obtain the methylene compound.

[0076] The present invention has no special limitation on the amount of water added, stirring rate and time for the water addition and stirring. The amount of water added, stirring rate and time commonly used by those skilled in the art can be adopted. In the examples of the present invention, the time for the water addition and stirring is 1 h. The present invention can cause crystallization of the product obtained by negative pressure concentration through water addition and stirring.

[0077] The present invention has no special limitation on the operations of filtration, washing, and drying, and the operations of filtration, washing, and drying commonly used by those skilled in the art can be adopted. As an embodiment of the present invention, the solvent for washing can be water; the water washing can be carried out until the washing liquid is neutral. As an embodiment of the present invention, the drying temperature can be 70-80°C; the drying time can be 6 h.

[0078] Through filtration, washing, and drying, the present invention can wash away the excess acid and unreacted raw materials in the reaction process, ensuring the yield and purity of methylprednisolone prepared subsequently.

[0079] After obtaining the methylene compound, the present invention mixes the methylene compound, solvent 2, catalyst 2, catalyst 3, and hydrogen donor to carry out a hydrogenation reaction to obtain the 6a-methyl compound.

[0080] As an embodiment of the present invention, the solvent 2 can be a mixed solvent of solvent A and solvent B; the solvent A can be dichloromethane or chloroform; the solvent B can be tetrahydrofuran, methanol, ethanol, or acetonitrile; the mass ratio of solvent A to solvent B can be (3-9):1; the catalyst 2 can be palladium on carbon with a palladium mass percentage of 3-10%, PtO 2 or Pd(OAc) 2 ; the catalyst 3 can be p-toluenesulfonic acid, sulfuric acid, perchloric acid, or methanesulfonic acid; the hydrogen donor is hydrogen, ammonium formate, boric acid, or formic acid. In the present invention, the hydrogen donor contains active hydrogen for the hydrogenation reaction. By limiting the types of the methylene compound, solvent 2, catalyst 2, catalyst 3, and hydrogen donor to the above ranges, the present invention can avoid using cyclohexene as the hydrogen donor, reduce the use of toxic raw materials in the reaction process, and ensure the smooth progress of the hydrogenation reaction.

[0081] As an embodiment of the present invention, the mass ratio of the methylene compound, solvent 2, and catalyst 2 can be 1:(3-10):(0.02-0.1), can also be 1:(4-8):(0.04-0.08), and can also be 1:(5-6):(0.05-0.06); the molar ratio of the methylene compound, catalyst 3, and hydrogen donor can be 1:(0.01-0.05):(1-2), can also be 1:(0.02-0.04):(1.2-1.8), and can also be 1:(0.03-0.04):(1.4-1.6). By limiting the mass ratio of the methylene compound, solvent 2, and catalyst 2 and the molar ratio of the methylene compound, catalyst 3, and hydrogen donor to the above ranges, the present invention can improve the purity and yield of the hydrogenation reaction product (6a-methyl compound).

[0082] As an embodiment of the present invention, when the hydrogen donor is hydrogen, it can be mixed with the methylene compound, solvent 2, catalyst 2 and catalyst 3 by continuously introducing hydrogen into the reaction solution at atmospheric pressure or under a hydrogen pressure of 0.1 Mpa or less.

[0083] As an embodiment of the present invention, the temperature of the hydrogenation reaction can be 5 to 35 °C, can also be 15 to 25 °C, and can also be 20 °C. The present invention has no special limitation on the time of the hydrogenation reaction, and it can be stopped after detecting the end of the reaction by thin layer chromatography (TLC detection). Limiting the temperature of the hydrogenation reaction within the above range can ensure the smooth progress of the hydrogenation reaction.

[0084] In the present invention, the chemical changes occurring during the hydrogenation reaction are shown in Formula 4:

[0085]

[0086] After the hydrogenation reaction ends, the present invention preferably further includes successively filtering, concentrating under negative pressure, adding water and stirring, filtering, washing and drying the reaction solution of the hydrogenation reaction to obtain the 6a-methyl compound.

[0087] In the present invention, the solid catalyst in the reaction solution can be removed by filtration.

[0088] As an embodiment of the present invention, the range of the negative pressure for the negative pressure concentration is the same as the range of the negative pressure for the negative pressure concentration described above, and will not be elaborated here.

[0089] The present invention has no special limitation on the amount of water added, the stirring rate and the time for adding water and stirring, and the amount of water added, the stirring rate and the time commonly used by those skilled in the art can be adopted. In the examples of the present invention, the time for adding water and stirring is 1 h. In the present invention, crystallization of the product obtained by concentrating under negative pressure can be achieved by adding water and stirring.

[0090] The present invention has no special limitation on the operations of filtration, washing and drying, and the operations of filtration, washing and drying commonly used by those skilled in the art can be adopted. As an embodiment of the present invention, the solvent for washing can be water; the water washing can be carried out until the washing liquid is neutral. As an embodiment of the present invention, the drying temperature can be 70 to 80 °C; the drying time can be 6 h.

[0091] In the present invention, the excess raw materials and solvents in the reaction process can be washed away by filtration, washing and drying, ensuring the yield and purity of the methylprednisolone prepared subsequently.

[0092] After obtaining the 6a-methyl compound, the present invention mixes the 6a-methyl compound, solvent 3, catalyst 4 and oxidant to carry out an oxidation reaction to obtain the 1,2-dehydrogenated compound.

[0093] In the present invention, the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone; the catalyst 4 is trifluoroacetic acid, N,O-bis(trimethylsilyl)acetamide or trimethylchlorosilane. Limiting the types of the oxidant and the catalyst 4 within the above ranges in the present invention can ensure a high yield of 1,2-dehydrogenated product. The present invention uses 2,3-dichloro-5,6-dicyanobenzoquinone as the oxidant, and selective dehydrogenation can be achieved through negative hydrogen transfer or hydrogen radical transfer to obtain 1,2-dehydrogenated product with a high reaction yield.

[0094] The specific reaction mechanism of the negative hydrogen transfer is as shown in Formula 5

[0095]

[0096] The specific reaction mechanism of the hydrogen radical transfer is as shown in Formula 6

[0097]

[0098] As an embodiment of the present invention, the solvent 3 is tetrahydrofuran, ethyl acetate, toluene, dioxane or methylcyclohexane. Limiting the types of the solvent 3 within the above ranges in the present invention can ensure the smooth progress of the oxidation reaction.

[0099] As an embodiment of the present invention, the mass ratio of the 6a-methyl compound to the solvent 3 can be 1:(5 - 20), can also be 1:(10 - 15), and can also be 1:(12 - 14); the molar ratio of the 6a-methyl compound, the catalyst 4 and the oxidant can be 1:(0.01 - 0.05):(1 - 1.5), can also be 1:(0.02 - 0.04):(1.1 - 1.4), and can also be 1:(0.03 - 0.04):(1.2 - 1.3). Limiting the mass ratio of the 6a-methyl compound to the solvent 3 and the molar ratio of the 6a-methyl compound, the catalyst 4 and the oxidant within the above ranges in the present invention can improve the purity and yield of the 1,2-dehydrogenated product.

[0100] As an embodiment of the present invention, the temperature of the oxidation reaction can be 0 - 65 °C, can also be 10 - 45 °C, and can also be 20 - 30 °C. The present invention has no special limitation on the time of the oxidation reaction, and it can be carried out until the reaction is detected to be completed by thin layer chromatography (TLC detection). Limiting the temperature of the oxidation reaction within the above ranges in the present invention can ensure the smooth progress of the oxidation reaction.

[0101] In the present invention, the chemical changes occurring during the oxidation reaction are as shown in Formula 7:

[0102]

[0103] After the oxidation reaction ends, the present invention preferably further includes successively filtering, concentrating under negative pressure, adding water and stirring, filtering, washing, and drying the reaction solution of the oxidation reaction to obtain 1,2-dehydro product.

[0104] In the present invention, the remaining oxidant in the reaction solution can be removed by filtration.

[0105] As an embodiment of the present invention, before the negative pressure concentration, an aqueous solution of sodium bisulfite at 10 wt% can be added to the filtrate after filtration. After separating the aqueous layer, an aqueous solution of sodium bisulfite at 10 wt% is added again for washing once, and then the aqueous layer is separated to obtain an organic layer, and the obtained organic layer is concentrated under negative pressure.

[0106] As an embodiment of the present invention, the selection range of the negative pressure for the negative pressure concentration is the same as the selection range of the negative pressure for the above-mentioned negative pressure concentration, and will not be elaborated here.

[0107] The present invention has no special limitation on the amount of water added, stirring rate, and time for the addition of water and stirring. The amount of water added, stirring rate, and time commonly used by those skilled in the art can be adopted. In the examples of the present invention, the time for the addition of water and stirring is 1 h. By adding water and stirring in the present invention, the product obtained by negative pressure concentration can be crystallized.

[0108] The present invention has no special limitation on the operations of filtration, washing, and drying. The operations of filtration, washing, and drying commonly used by those skilled in the art can be adopted. As an embodiment of the present invention, the solvent for washing can be water; the water washing can be carried out until the washing liquid is neutral. As an embodiment of the present invention, the drying temperature can be 70 - 80 °C; the drying time can be 6 h.

[0109] In the present invention, the excess raw materials and solvents in the reaction process can be washed away by filtration, washing, and drying, ensuring the yield and purity of methylprednisolone prepared subsequently.

[0110] After obtaining the 1,2-dehydro product, the present invention mixes the 1,2-dehydro product, solvent 4, catalyst 5, and reducing agent for a reduction reaction to obtain a crude product of methylprednisolone acetate.

[0111] In the present invention, the catalyst 5 is calcium chloride, magnesium chloride, zinc chloride, or barium chloride. By limiting the types of catalysts within the above range, a crude product of methylprednisolone acetate with a relatively high yield can be obtained.

[0112] As an embodiment of the present invention, the solvent 4 can be a mixed solvent of solvent A and solvent C; the solvent C can be methanol or ethanol; the solvent A is dichloromethane or chloroform; the mass ratio of solvent A to solvent C can be (2 - 5):1; the reducing agent can be potassium borohydride or sodium borohydride. Limiting the types of solvent 4 and the reducing agent within the above ranges in the present invention can ensure the smooth progress of the reduction reaction.

[0113] As an embodiment of the present invention, the mass ratio of the 1,2-dehydro product to the solvent 4 can be 1:(5 - 20), can also be 1:(10 - 15), and can also be 1:(12 - 14); the molar ratio of the 1,2-dehydro product, the catalyst 5, and the reducing agent can be 1:(0.1 - 0.5):(1 - 2), can also be 1:(0.2 - 0.4):(1.2 - 1.8), and can also be 1:(0.2 - 0.3):(1.4 - 1.6). Limiting the mass ratio of the 1,2-dehydro product to the solvent 4 and the molar ratio of the 1,2-dehydro product, the catalyst 5, and the reducing agent within the above ranges in the present invention can improve the purity and yield of the crude methylprednisolone acetate.

[0114] As an embodiment of the present invention, the reducing agent can be added in batches during the reduction reaction; the number of batches for the batch addition can be 6 times. By adding the reducing agent in batches in the present invention, the degree of the reduction reaction can be improved.

[0115] As an embodiment of the present invention, the temperature of the reduction reaction can be -40 to -30°C, can also be -38 to -32°C, can also be -36 to -34°C, and can also be -35°C. The present invention has no special limitation on the time of the reduction reaction, and it can be stopped after detecting the end of the reaction by thin layer chromatography (TLC detection). Limiting the temperature of the reduction reaction within the above ranges in the present invention can ensure the smooth progress of the reduction reaction.

[0116] In the present invention, under the conditions of using calcium chloride, magnesium chloride, zinc chloride, or barium chloride as the catalyst and low temperature (-40 to -30°C) reduction for the 1,2-dehydro product, the 3-keto group forms a conjugated system with the 1,2- and 4,5-double bonds and is not easily reduced. Due to the large steric hindrance of the 20-keto group, the proportion of reduction is small, manifested as about 2% of over-hydrogenated impurities, which can be removed by the adsorption (refining) of the subsequent adsorbent. It is possible to prepare the crude methylprednisolone acetate without the need for protection and deprotection, and the reaction yield is high.

[0117] In the present invention, the chemical changes occurring during the reduction reaction are shown in Formula 8:

[0118]

[0119] After the reduction reaction is completed, the present invention preferably further includes subjecting the reaction solution of the reduction reaction to negative pressure concentration, adding water and stirring, filtration, washing, and drying in sequence to obtain crude methylprednisolone acetate.

[0120] As an embodiment of the present invention, before the negative pressure concentration, an acetic acid aqueous solution with a concentration of 30-60 wt% can be added to the reaction solution of the reduction reaction to adjust the pH of the reaction solution to 6.

[0121] As an embodiment of the present invention, the selection range of the negative pressure for the negative pressure concentration is the same as the selection range of the negative pressure for the above-mentioned negative pressure concentration, and will not be elaborated here.

[0122] The present invention has no special limitation on the amount of water added, the stirring rate, and the time for adding water and stirring. The amount of water added, the stirring rate, and the time commonly used by those skilled in the art can be adopted. In the examples of the present invention, the time for adding water and stirring is 1 h. By adding water and stirring in the present invention, the product obtained by negative pressure concentration can be crystallized.

[0123] The present invention has no special limitation on the operations of filtration, washing, and drying. The operations of filtration, washing, and drying commonly used by those skilled in the art can be adopted. As an embodiment of the present invention, the solvent for washing can be water; the water washing can be carried out until the washing liquid is neutral. As an embodiment of the present invention, the drying temperature can be 70-80 °C; the drying time can be 6 h.

[0124] By filtration, washing, and drying in the present invention, the excess raw materials and solvents in the reaction process can be washed away, ensuring the yield and purity of the methylprednisolone prepared subsequently.

[0125] After obtaining the crude methylprednisolone acetate, the present invention mixes the crude methylprednisolone acetate, solvent 4, and adsorbent for adsorption, and then carries out crystallization and recrystallization in sequence to obtain high-quality methylprednisolone acetate.

[0126] In the examples of the present invention, before the crude methylprednisolone acetate is mixed with solvent 4 and adsorbent, methanol can be added first, stirred at 25-35 °C for 1 h, filtered, and then used.

[0127] As an embodiment of the present invention, the adsorbent can be activated carbon or neutral alumina. The present invention limits the type of adsorbent within the above range to adsorb the impurities in the crude methylprednisolone acetate.

[0128] As an embodiment of the present invention, the mass ratio of the crude methylprednisolone acetate to the activated carbon may be 1:(0.01 - 0.05), may also be 1:(0.02 - 0.04), and may also be 1:(0.03 - 0.04); the mass ratio of the crude methylprednisolone acetate to the neutral alumina may be 1:(0.1 - 0.5), may also be 1:(0.2 - 0.4), and may also be 1:(0.3 - 0.4); the mass ratio of the crude methylprednisolone acetate and the solvent 4 may be 1:(5 - 20), may also be 1:(10 - 15), and may also be 1:(12 - 14). By limiting the mass ratio of the crude methylprednisolone acetate to the adsorbent and the mass ratio of the crude methylprednisolone acetate and the solvent 4 within the above ranges, the present invention can ensure obtaining high-yield and high-purity refined methylprednisolone acetate.

[0129] In the present invention, the adsorption is preferably carried out under stirring conditions. The present invention has no special limitation on the rotation speed of the stirring, and the rotation speed well-known to those skilled in the art can be adopted.

[0130] After adsorption, the present invention preferably further includes successively filtering and concentrating under negative pressure the reaction solution of the adsorption.

[0131] The present invention has no special limitation on the operation of the filtration, and the filtration operation well-known to those skilled in the art can be adopted.

[0132] As an embodiment of the present invention, the selection range of the negative pressure for the negative pressure concentration is the same as the selection range of the negative pressure for the negative pressure concentration described above, and will not be elaborated here.

[0133] As an embodiment of the present invention, the crystallization can be crystallization by cooling; the temperature for the crystallization by cooling is below 10°C.

[0134] After crystallization, the present invention preferably further includes successively filtering, recrystallizing and drying the crystallization product to obtain refined methylprednisolone acetate.

[0135] As an embodiment of the present invention, the number of times of recrystallization can be 1 - 2 times; the solvent for recrystallization can be a mixed solvent of dichloromethane and methanol. The present invention has no special limitation on the mixing ratio of dichloromethane and methanol, and any ratio can be adopted. The present invention can improve the purity of the refined methylprednisolone acetate through recrystallization.

[0136] The temperature and time ranges for drying in the present invention are the same as the temperature and time ranges for drying described above, and will not be elaborated here.

[0137] After obtaining the refined methylprednisolone acetate, the present invention mixes the refined methylprednisolone acetate, the solvent 5 and the alkali solution to carry out a hydrolysis reaction and then crystallizes to obtain crude methylprednisolone.

[0138] As an embodiment of the present invention, the solvent 5 is a mixed solvent of solvent A and solvent C; the solvent A can be dichloromethane or chloroform; the solvent C can be methanol or ethanol. The alkali solution can be a mixture of solution D and solution E; the solution D can be a methanol / ethanol solution of sodium hydroxide / potassium hydroxide; the concentration of the solution D can be 0.05 wt%; the solution E can be an aqueous solution of potassium carbonate / sodium carbonate; the concentration of the solution E can be 0.01 wt%; the mass ratio of the solution D to the solution E can be (5 - 10):1. Limiting the types and ratios of the solvent 5 and the alkali solution within the above ranges in the present invention can ensure the smooth progress of the hydrolysis reaction.

[0139] As an embodiment of the present invention, the mass ratio of methylprednisolone acetate fine product to the solvent 5 can be 1:(5 - 20), can also be 1:(10 - 15), and can also be 1:(12 - 14); the mass ratio of methylprednisolone acetate fine product to the alkali solution can be 1:(0.5 - 2), can also be 1:(0.8 - 1.5), and can also be 1:(1.0 - 1.2). Limiting the mass ratio of methylprednisolone acetate fine product to the solvent 5 and the mass ratio of methylprednisolone acetate fine product to the alkali solution within the above ranges in the present invention can improve the yield and purity of methylprednisolone.

[0140] As an embodiment of the present invention, the hydrolysis reaction is preferably carried out under nitrogen protection; the temperature of the hydrolysis reaction can be -20 to 0 °C, can also be -15 to -5 °C, and can also be -12 to -10 °C. The present invention has no special limitation on the time of the hydrolysis reaction, and it can be carried out until the reaction is detected to be completed by thin layer chromatography (TLC detection). Limiting the temperature of the hydrolysis reaction within the above ranges in the present invention can ensure the smooth progress of the hydrolysis reaction.

[0141] In the present invention, the chemical changes occurring during the reduction reaction are shown in Formula 9:

[0142]

[0143] After the hydrolysis reaction is completed, the present invention preferably concentrates the product of the hydrolysis reaction under negative pressure.

[0144] As an embodiment of the present invention, the selection range of the negative pressure for the negative pressure concentration is the same as the selection range of the negative pressure for the above-mentioned negative pressure concentration, and will not be elaborated here.

[0145] As an embodiment of the present invention, the crystallization can be crystallization by cooling; the temperature for the crystallization by cooling is below 10 °C.

[0146] After crystallization, the present invention preferably further includes filtering and drying the crystallization product in sequence to obtain crude methylprednisolone.

[0147] The temperature and time ranges for drying in the present invention are the same as those for the above-mentioned drying, and will not be elaborated here.

[0148] After obtaining the crude methylprednisolone, the present invention mixes the crude methylprednisolone, solvent 5 and adsorbent for adsorption and then crystallization to obtain methylprednisolone.

[0149] In the examples of the present invention, before mixing the crude methylprednisolone with solvent 5 and adsorbent, methanol can be added first, stirred at 25 - 35 °C for 1 hour, filtered and then used.

[0150] In the process of preparing methylprednisolone from the crude methylprednisolone in the present invention, the type of the adsorbent is the same as that in the process of preparing high-quality acetic acid methylprednisolone from crude acetic acid methylprednisolone, and will not be elaborated here.

[0151] In the present invention, the selection range of the ratio of the crude methylprednisolone to solvent 5 and adsorbent is the same as the selection range of the ratio of the crude acetic acid methylprednisolone to solvent 4 and adsorbent above, and will not be elaborated here.

[0152] In the present invention, the adsorption is preferably carried out under stirring conditions. The present invention has no special limitation on the stirring speed, and the stirring speed well-known to those skilled in the art can be adopted.

[0153] After adsorption, the present invention preferably further includes filtering and negative pressure concentration of the reaction solution of the adsorption in sequence.

[0154] The present invention has no special limitation on the filtration operation, and the filtration operation well-known to those skilled in the art can be adopted.

[0155] As an embodiment of the present invention, the selection range of the negative pressure for the negative pressure concentration is the same as the selection range of the negative pressure for the above-mentioned negative pressure concentration, and will not be elaborated here.

[0156] As an embodiment of the present invention, the crystallization can be cooling crystallization; the temperature of the cooling crystallization is below 10 °C.

[0157] After crystallization, the present invention preferably further includes filtering and drying the crystallization product in sequence to obtain methylprednisolone.

[0158] The temperature and time ranges for drying in the present invention are the same as those for the above-mentioned drying, and will not be elaborated here.

[0159] In the hydrogenation process of the methylene compound of the present invention, hydrogen, ammonium formate, boric acid or formic acid is used as a hydrogen donor, which can avoid the use of cyclohexene and make the preparation process more environmentally friendly; then 2,3-dichloro-5,6-dicyanobenzoquinone is used as an oxidant, and selective dehydrogenation is carried out under the action of a specific type of catalyst 4 to prepare a high-purity 1,2-dehydrogenated product in high yield, thereby ensuring the yield and purity of the subsequent reaction products; then selective reduction is directly carried out under the catalysis of a certain temperature and catalyst to prepare crude methylprednisolone acetate in high yield, and finally, through adsorption purification and purification after hydrolysis, methylprednisolone is prepared in high yield while improving the purity.

[0160] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0161] Example 1

[0162] A preparation method of methylprednisolone:

[0163] (1) Mix 10 g of cortisone acetate (24.9 mmol), 180 g of methanol (solvent 1 and etherifying agent), 5 g of trimethyl orthoformate and 0.01 g of hydrochloric acid, stir at 35 °C for 2 hours for etherification reaction, perform TLC detection, confirm that the reaction is complete, then add 2.0 g of diethylamine (27.4 mmol) and 2.5 g of aqueous formaldehyde solution (30.8 mmol), stir at 35 °C for 2 hours for Mannich reaction, perform TLC detection, confirm that the reaction is complete, then add 18 wt% hydrochloric acid to adjust the pH of the mixed solution to 2 for decomposition reaction, then concentrate under negative pressure to a thick state at -0.09 MPa, add 50 ml of water, stir and crystallize for 1 hour, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 10.2 g of methylene compound; the mass ratio of cortisone acetate, solvent 1 (methanol), etherifying agent (methanol), dehydrating agent (trimethyl orthoformate) and catalyst 1 (hydrochloric acid) is 1:17:1:0.5:0.001; the molar ratio of cortisone acetate, organic secondary amine (diethylamine) and aldehyde (formaldehyde) is 1:1.1:1.24;

[0164] (2) Take 10 g (24.2 mmol) of the methylene compound obtained in step (1), 20 g of dichloromethane, 10 g of methanol, 0.8 g of palladium on carbon with 3% palladium by mass, 0.5 g of sulfuric acid (5 mmol), and 2.0 g of formic acid (38.3 mmol), mix them, and stir at 20 °C for 8 hours for the hydrogenation reaction. Conduct TLC detection to confirm the completion of the reaction, then filter to remove the palladium on carbon. Concentrate the filtrate under a negative pressure of -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 9.8 g of the 6a-methyl compound; the mass ratio of the methylene compound, solvent 2 (dichloromethane and methanol), and catalyst 2 (palladium on carbon with 3% palladium by mass) is 1:5:0.08; the molar ratio of the methylene compound, catalyst 3 (sulfuric acid), and hydrogen donor (formic acid) is 1:0.2:1.58;

[0165] (3) Take 10 g (24.2 mmol) of the 6a-methyl compound obtained in step (2), 100 g of tetrahydrofuran, 0.05 g of BSA (N,O-bis(trimethylsilyl)acetamide, 0.25 mmol), and 5.8 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone, 25.5 mmol), mix them, and stir at 0 °C for 8 hours for the oxidation reaction. Conduct TLC detection to confirm the completion of the reaction, then filter to remove hydroquinone. Concentrate the filtrate under a negative pressure of -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 9.2 g of the 1,2-dehydro compound; the mass ratio of the 6a-methyl compound and solvent 3 (tetrahydrofuran) is 1:10; the molar ratio of the 6a-methyl compound, catalyst 4 (BSA), and oxidant (DDQ) is 1:0.01:1.05;

[0166] (4) Take 10 g (24.2 mmol) of the 1,2-dehydro compound obtained in step (3), 30 g of dichloromethane, 10 g of methanol, and 0.4 g of zinc chloride (2.9 mmol), cool down to -40 °C, add 1.8 g of potassium borohydride (33.3 mmol) in 6 portions, and stir for 2 hours for the reduction reaction. Conduct TLC detection to confirm the completion of the reaction, then add 50% aqueous acetic acid solution to adjust the pH to 6, concentrate under a negative pressure of -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain the crude product of methylprednisolone acetate; the mass ratio of the 1,2-dehydro compound and solvent 4 (dichloromethane and methanol) is 1:5; the molar ratio of the 1,2-dehydro compound, catalyst 5 (zinc chloride), and reducing agent (potassium borohydride) is 1:0.12:1.38;

[0167] (5) Add 10 g of methanol to all the crude methylprednisolone acetate obtained in step (4), stir at 25 °C for 1 hour, filter, add 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon to the filter cake, reflux for decolorization and adsorption for 1 hour, then filter. Concentrate the filtrate under negative pressure at -0.09 MPa until it becomes thick, cool to below 10 °C for crystallization, filter, and then recrystallize the filter cake with dichloromethanol once, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 8.1 g of high-quality methylprednisolone acetate; the mass ratio of the crude methylprednisolone acetate to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone acetate to solvent 4 (dichloromethane and methanol) is 1:8;

[0168] (6) Take 10 g (24.0 mmol) of the high-quality methylprednisolone acetate obtained in step (5), 50 g of dichloromethane, and 20 g of methanol. Under nitrogen protection, cool to -20 °C, add dropwise 10 g of a methanol solution of 0.05% sodium hydroxide, and 10 g of a 0.01% aqueous sodium carbonate solution. Hydrolyze at -15 °C for 2 hours, perform TLC detection, confirm that the reaction is complete, add 50% acetic acid aqueous solution to adjust the pH to 6, concentrate under negative pressure at -0.09 MPa until it becomes thick, add 50 ml of water and stir for crystallization for 1 hour, filter, wash with water until neutral to obtain crude methylprednisolone; the mass ratio of the high-quality methylprednisolone acetate to solvent 5 (dichloromethane and methanol) is 1:10; the mass ratio of the high-quality methylprednisolone acetate to the alkali solution is 1:2;

[0169] (7) Add 6 g of methanol to all the crude methylprednisolone obtained in step (6), stir at 25 °C for 1 hour, filter, add 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon to the filter cake, reflux for decolorization and adsorption for 1 hour, then filter. Concentrate the filtrate under negative pressure at -0.09 MPa until it becomes thick, cool to below 10 °C for crystallization, filter, and dry at 80 °C for 6 hours to obtain 8.0 g of methylprednisolone; the mass ratio of the crude methylprednisolone to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone to solvent 5 (dichloromethane and methanol) is 1:8.

[0170] The methylprednisolone obtained in Example 1 was tested using a Shimadzu LC-2030CPlus high-performance liquid chromatograph, and the obtained liquid chromatogram is as Figure 1 shown, and the test data are shown in Table 1. It can be seen from Figure 1 Table 1 that the purity of methylprednisolone in Example 1 is 99.847%;

[0171] Table 1 Liquid chromatographic test data of methylprednisolone prepared in Example 1

[0172]

[0173] The yield of methylprednisolone obtained in Example 1 is 59.6%.

[0174] Example 2

[0175] A preparation method of methylprednisolone:

[0176] (1) Mix 10 g of cortisone acetate (24.9 mmol), 200 g of ethanol (solvent 1 and etherifying agent), 5 g of trimethyl orthoformate and 0.015 g of p-toluenesulfonic acid, stir at 35 °C for 2 hours for etherification reaction, conduct TLC detection, confirm that the reaction is complete, then add 2.0 g of dimethylamine (27.4 mmol) and 0.9 g of paraformaldehyde (30.0 mmol), stir at 35 °C for 4 hours for Mannich reaction, conduct TLC detection, confirm that the reaction is complete, add 10 wt% sulfuric acid to adjust the pH of the mixed solution to 2 for decomposition reaction, then concentrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir and crystallize for 1 hour, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 10.1 g of methylene compound; the mass ratio of cortisone acetate, solvent 1 (ethanol), etherifying agent (ethanol), dehydrating agent (trimethyl orthoformate) and catalyst 1 (p-toluenesulfonic acid) is 1:19:1:0.5:0.0015; the molar ratio of cortisone acetate, organic secondary amine (diethylamine) and aldehyde (formaldehyde) is 1:1.1:1.2;

[0177] (2) Take 10 g (24.2 mmol) of the methylene compound obtained in step (1), 30 g of chloroform, 0 g of ethanol, 0.5 g of palladium-carbon with a palladium mass percentage of 5%, 0.2 g of p-toluenesulfonic acid (1.16 mmol) and 2.5 g of ammonium formate (39.7 mmol), mix and stir at 20 °C for 8 hours for hydrogenation reaction, conduct TLC detection, confirm that the reaction is complete, then filter to remove palladium-carbon, concentrate the filtrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir and crystallize for 1 hour, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 9.8 g of 6a-methyl compound; the mass ratio of the methylene compound, solvent 2 (chloroform and ethanol) and catalyst 2 (palladium-carbon with a palladium mass percentage of 3%) is 1:6:0.05; the molar ratio of the methylene compound, catalyst 3 (p-toluenesulfonic acid) and hydrogen donor (ammonium formate) is 1:0.048:1.64;

[0178] (3) Take 10 g (24.0 mmol) of the 6a-methyl compound obtained in step (2), 150 g of toluene, 0.05 g of TFA (trifluoroacetic acid, 0.44 mmol), and 6.0 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone, 26.4 mmol), mix them, stir at 60 °C for 2 hours for an oxidation reaction, conduct TLC detection, confirm that the reaction is complete, add 20 ml of 10% aqueous sodium bisulfite solution, then filter to remove hydroquinone, separate the aqueous layer, wash with 20 ml of 10% aqueous sodium bisulfite solution once again, separate the aqueous layer, concentrate the organic layer under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 9.0 g of the 1,2-dehydrogenated product; the mass ratio of the 6a-methyl compound to solvent 3 (toluene) is 1:15; the molar ratio of the 6a-methyl compound, catalyst 4 (TFA), and oxidant (DDQ) is 1:0.018:1.1;

[0179] (4) Take 10 g (24.2 mmol) of the 1,2-dehydrogenated product obtained in step (3), 60 g of chloroform, 20 g of ethanol, and 0.3 g of calcium chloride (2.7 mmol), cool down to -40 °C, add 1.2 g of sodium borohydride (31.6 mmol) in 6 portions, stir for 2 hours for a reduction reaction, conduct TLC detection, confirm that the reaction is complete, then add 50% aqueous acetic acid solution to adjust the pH to 6, concentrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain crude methylprednisolone acetate; the mass ratio of the 1,2-dehydrogenated product to solvent 4 (chloroform and ethanol) is 1:8; the molar ratio of the 1,2-dehydrogenated product, catalyst 5 (calcium chloride), and reducing agent (sodium borohydride) is 1:0.11:1.31;

[0180] (5) Add 10 g of methanol to all of the crude methylprednisolone acetate obtained in step (4), stir at 35 °C for 1 hour, filter, add the filter cake to 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon, reflux and decolorize by adsorption for 1 hour, then filter, concentrate the filtrate under negative pressure at -0.09 MPa to a thick state, cool down to below 10 °C to crystallize, after filtration, recrystallize the filter cake with dichloromethanol once again, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 8.2 g of high-quality methylprednisolone acetate; the mass ratio of the crude methylprednisolone acetate to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone acetate to solvent 4 (dichloromethane and methanol) is 1:8;

[0181] (6) Take 10 g (24.0 mmol) of the methylprednisolone acetate fine product obtained in step (5), 50 g of chloroform, and 20 g of ethanol. Under nitrogen protection, cool the mixture to -20°C, add dropwise 10 g of a methanol solution of 0.05% potassium hydroxide, and 10 g of an aqueous solution of 0.01% potassium carbonate. Carry out hydrolysis reaction at -10°C for 2 hours, perform TLC detection, confirm that the reaction is complete, add 50% acetic acid aqueous solution to adjust the pH to 6, concentrate under negative pressure to a thick state at -0.09 MPa, add 50 ml of water, stir for 1 hour to crystallize, filter, and wash with water until neutral to obtain the crude methylprednisolone; the mass ratio of the methylprednisolone acetate fine product to solvent 5 (chloroform and ethanol) is 1:12; the mass ratio of the methylprednisolone acetate fine product to the alkali solution is 1:2;

[0182] (7) Add 6 g of methanol to all of the crude methylprednisolone obtained in step (6), stir at 25 - 35°C for 1 hour, filter, add 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon to the filter cake, reflux and decolorize and adsorb for 1 hour, then filter. Concentrate the filtrate to a thick state under negative pressure at -0.09 MPa, cool to below 10°C to crystallize, filter, and dry at 80°C for 6 hours to obtain 8.0 g of methylprednisolone; the mass ratio of the crude methylprednisolone to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone to solvent 5 (dichloromethane and methanol) is 1:8.

[0183] The methylprednisolone obtained in Example 2 was tested using a Shimadzu LC-2030CPlus high-performance liquid chromatograph, and the obtained liquid chromatogram is as Figure 2 shown. The test data are shown in Table 2. From Figure 2 Table 2, it can be seen that the purity of methylprednisolone in Example 2 is 99.778%;

[0184] Table 2 Liquid chromatographic test data of methylprednisolone prepared in Example 2

[0185]

[0186]

[0187] The yield of methylprednisolone obtained in Example 2 is 58.4%.

[0188] Example 3

[0189] A method for preparing methylprednisolone:

[0190] (1) 10 g of cortisone acetate (24.9 mmol), 100 g of tetrahydrofuran, 1 g of ethanol (21.7 mmol), 7 g of triethyl orthoacetate, and 0.015 g of sulfuric acid were mixed and stirred at 40 °C for 2 hours for etherification reaction. TLC detection was carried out to confirm the completion of the reaction. Then, 3.0 g of N-methylaniline (28.0 mmol) and 0.9 g of paraformaldehyde (30.0 mmol) were added and stirred at 40 °C for 4 hours for Mannich reaction. TLC detection was carried out to confirm the completion of the reaction. Then, 20 wt% sulfuric acid was added to adjust the pH of the mixed solution to 2 for decomposition reaction. Then, it was concentrated under negative pressure to a thick state at -0.09 MPa, 50 ml of water was added and stirred for 1 hour for crystallization, filtered, washed with water until neutral, and dried at 80 °C for 6 hours to obtain 10.1 g of methylene compound; the mass ratio of cortisone acetate, solvent 1 (tetrahydrofuran), etherifying agent (ethanol), dehydrating agent (triethyl orthoacetate), and catalyst 1 (sulfuric acid) is 1:10:0.1:0.7:0.0015; the molar ratio of cortisone acetate, organic secondary amine (N-methylaniline), and aldehyde (paraformaldehyde) is 1:1.12:1.2;

[0191] (2) 10 g (24.2 mmol) of the methylene compound obtained in step (1), 50 g of chloroform, 20 g of ethanol, 0.5 g of 5% palladium on carbon, 0.2 g of p-toluenesulfonic acid (1.16 mmol), and 0.04 g of hydrogen (100 mmol) were mixed and stirred at 20 °C for 8 hours for hydrogenation reaction. TLC detection was carried out to confirm the completion of the reaction. Then, it was filtered to remove palladium on carbon, and the filtrate was concentrated under negative pressure to a thick state at -0.09 MPa, 50 ml of water was added and stirred for 1 hour for crystallization, filtered, washed with water until neutral, and dried at 80 °C for 6 hours to obtain 9.8 g of 6a-methyl compound; the mass ratio of the methylene compound, solvent 2 (chloroform and ethanol), and catalyst 2 (5% palladium on carbon) is 1:6:0.05; the molar ratio of the methylene compound, catalyst 3 (p-toluenesulfonic acid), and hydrogen donor (hydrogen) is 1:0.048:1.65;

[0192] (3) Take 10 g (24.0 mmol) of the 6a-methyl compound obtained in the step (2), 100 g of ethyl acetate, 0.05 g of TMCS (trimethylchlorosilane, 0.46 mmol), and 6.0 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone, 26.4 mmol), mix them, stir at 10 °C for 6 hours for the oxidation reaction, conduct TLC detection, confirm that the reaction is complete, add 20 ml of 10% aqueous sodium bisulfite solution, then filter to remove hydroquinone, separate the aqueous layer, wash with 20 ml of 10% aqueous sodium bisulfite solution once again, separate the aqueous layer, concentrate the organic layer under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 8.9 g of 1,2-dehydro compound; the mass ratio of the 6a-methyl compound to the solvent 3 (ethyl acetate) is 1:10; the molar ratio of the 6a-methyl compound, the catalyst 4 (TMCS), and the oxidant (DDQ) is 1:0.019:1.1;

[0193] (4) Take 10 g (24.2 mmol) of the 1,2-dehydro compound obtained in the step (3), 40 g of dichloromethane, 10 g of methanol, and 0.3 g of magnesium chloride (3.1 mmol), cool down to -40 °C, add 1.8 g of potassium borohydride (33.3 mmol) in 6 portions, stir for 2 hours for the reduction reaction, conduct TLC detection, confirm that the reaction is complete, then add 50% aqueous acetic acid solution to adjust the pH to 6, concentrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain crude methylprednisolone acetate; the mass ratio of the 1,2-dehydro compound to the solvent 4 (dichloromethane and methanol) is 1:7; the molar ratio of the 1,2-dehydro compound, the catalyst 5 (magnesium chloride), and the reducing agent (potassium borohydride) is 1:0.13:1.38;

[0194] (5) Add 10 g of methanol to all of the crude methylprednisolone acetate obtained in the step (4), stir at 25 °C for 1 hour, filter, add the filter cake to 50 g of dichloromethane and 30 g of methanol, reflux and decolorize and adsorb with 1 g of activated carbon for 1 hour, then filter, concentrate the filtrate under negative pressure at -0.09 MPa to a thick state, cool down to below 10 °C to crystallize, after filtration, recrystallize the filter cake with dichloromethanol once again, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 8.2 g of high-quality methylprednisolone acetate; the mass ratio of the crude methylprednisolone acetate to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone acetate to the solvent 4 (dichloromethane and methanol) is 1:8;

[0195] (6) Take 10 g (24.0 mmol) of the methylprednisolone acetate fine product obtained in step (5), 50 g of chloroform, and 20 g of ethanol. Under nitrogen protection, cool the temperature to -20°C, and dropwise add 10 g of a methanol solution of 0.05% potassium hydroxide and 10 g of an aqueous solution of 0.01% potassium carbonate. Hydrolyze at -10°C for 2 hours, perform TLC detection, confirm that the reaction is complete, add 50% acetic acid aqueous solution to adjust the pH to 6, and concentrate under negative pressure at -0.09 MPa until it becomes thick. Add 50 ml of water, stir and crystallize for 1 hour, filter, and wash with water until neutral to obtain the crude methylprednisolone; the mass ratio of the methylprednisolone acetate fine product to solvent 5 (chloroform and ethanol) is 1:12; the mass ratio of the methylprednisolone acetate fine product to the alkali solution is 1:2;

[0196] (7) Add 6 g of methanol to all of the crude methylprednisolone obtained in step (6), stir at 25°C for 1 hour, filter, add 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon to the filter cake, reflux and decolorize and adsorb for 1 hour, then filter. Concentrate the filtrate under negative pressure at -0.09 MPa until it becomes thick, cool to below 10°C to crystallize, filter, and dry at 80°C for 6 hours to obtain 8.2 g of methylprednisolone; the mass ratio of the crude methylprednisolone to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone to solvent 5 (dichloromethane and methanol) is 1:8.

[0197] The methylprednisolone obtained in Example 3 was tested using a Shimadzu LC-2030C Plus high-performance liquid chromatograph, and the obtained liquid chromatogram is as Figure 3 shown, and the test data are shown in Table 3. It can be seen from Figure 3 and Table 3 that the purity of methylprednisolone in Example 3 is 99.891%;

[0198] Table 3 Test data of methylprednisolone prepared in Example 3

[0199]

[0200] The yield of methylprednisolone obtained in Example 3 is 59.2%.

[0201] Example 4

[0202] A method for preparing methylprednisolone:

[0203] (1) Mix 10 g of cortisone acetate (24.9 mmol), 50 g of acetic acid, 2 g of methanol, 5 g of trimethyl orthoacetate, and 0.015 g of methanesulfonic acid, and stir at 30 °C for 2 hours for the etherification reaction. Conduct TLC detection to confirm the completion of the reaction. Then add 2.0 g of piperidine (27.4 mmol) and 0.9 g of aqueous formaldehyde solution (30.0 mmol), and stir at 30 °C for 4 hours for the Mannich reaction. Conduct TLC detection to confirm the completion of the reaction. Then add 10 wt% sulfuric acid to adjust the pH of the mixture to 2 for the decomposition reaction. Then concentrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir and crystallize for 1 hour, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 10.1 g of methylene compound; the mass ratio of cortisone acetate, solvent 1 (ethanol), etherifying agent (methanol), dehydrating agent (trimethyl orthoacetate), and catalyst 1 (methanesulfonic acid) is 1:5:0.2:0.5:0.0015; the molar ratio of cortisone acetate, organic secondary amine (piperidine), and aldehyde (formaldehyde) is 1:1.1:1.2;

[0204] (2) Take 10 g (24.2 mmol) of the methylene compound obtained in step (1), 20 g of chloroform, 10 g of tetrahydrofuran, 0.5 g of Pd(OAc) 2 , 0.1 g of perchloric acid (0.58 mmol), and 2.5 g of boric acid (39.7 mmol), mix and stir at 5 °C for 10 hours for the hydrogenation reaction. Conduct TLC detection to confirm the completion of the reaction. Then filter to remove palladium carbon. Concentrate the filtrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir and crystallize for 1 hour, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 9.7 g of 6a-methyl compound; the mass ratio of the methylene compound, solvent 2 (chloroform and tetrahydrofuran), and catalyst 2 (palladium carbon with 3% palladium by mass) is 1:3:0.05; the molar ratio of the methylene compound, catalyst 3 (perchloric acid), and hydrogen donor (boric acid) is 1:0.024:1.64

[0205] (3) Take 10 g (24.0 mmol) of the 6a-methyl compound obtained in step (2), 150 g of dioxane, 0.05 g of TFA (trifluoroacetic acid, 0.44 mmol), and 6.0 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone, 26.4 mmol), mix them, stir at 20 °C for 6 hours for an oxidation reaction, perform TLC detection, confirm that the reaction is complete, add 20 ml of 10% sodium bisulfite aqueous solution, then filter to remove hydroquinone, separate the aqueous layer, wash with 20 ml of 10% sodium bisulfite aqueous solution once again, separate the aqueous layer, concentrate the organic layer under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 9.0 g of 1,2-dehydrogenated product; the mass ratio of the 6a-methyl compound to solvent 3 (toluene) is 1:15; the molar ratio of the 6a-methyl compound, catalyst 4 (TFA), and oxidant (DDQ) is 1:0.018:1.1;

[0206] (4) Take 10 g (24.2 mmol) of the 1,2-dehydrogenated product obtained in step (3), 40 g of chloroform, 20 g of ethanol, and 0.3 g of calcium chloride (2.7 mmol), cool down to -30 °C, add 1.2 g of sodium borohydride (31.6 mmol) in 6 portions, stir for 2 hours for a reduction reaction, perform TLC detection, confirm that the reaction is complete, then add 50% acetic acid aqueous solution to adjust the pH to 6, concentrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for 1 hour to crystallize, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain crude methylprednisolone acetate; the mass ratio of the 1,2-dehydrogenated product to solvent 4 (chloroform and ethanol) is 1:8; the molar ratio of the 1,2-dehydrogenated product, catalyst 5 (calcium chloride), and reducing agent (sodium borohydride) is 1:0.11:1.31;

[0207] (5) Add 10 g of methanol to all of the crude methylprednisolone acetate obtained in step (4), stir at 25 °C for 1 hour, filter, add the filter cake to 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon, reflux and decolorize and adsorb for 1 hour, then filter, concentrate the filtrate under negative pressure at -0.09 MPa to a thick state, cool down to below 10 °C to crystallize, after filtration, recrystallize the filter cake with dichloromethanol once again, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 8.2 g of high-quality methylprednisolone acetate; the mass ratio of the crude methylprednisolone acetate to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone acetate to solvent 4 (dichloromethane and methanol) is 1:8;

[0208] (6) Take 10 g (24.0 mmol) of the methylprednisolone acetate fine product obtained in step (5), 60 g of chloroform, and 20 g of ethanol. Under nitrogen protection, cool the temperature to -20°C, dropwise add 10 g of a methanol solution of 0.05% potassium hydroxide, and 10 g of an aqueous solution of 0.01% potassium carbonate. Hydrolyze at -10°C for 2 hours, perform TLC detection, confirm that the reaction is complete, add 50% acetic acid aqueous solution to adjust the pH to 6, concentrate under negative pressure to a thick state at -0.09 MPa, add 50 ml of water, stir and crystallize for 1 hour, filter, and wash with water until neutral to obtain the crude methylprednisolone; the mass ratio of the methylprednisolone acetate fine product to solvent 5 (chloroform and ethanol) is 1:12; the mass ratio of the methylprednisolone acetate fine product to the alkali solution is 1:2;

[0209] (7) Add 6 g of methanol to all of the crude methylprednisolone obtained in step (6), stir at 25 - 35°C for 1 hour, filter, add 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon to the filter cake, reflux and decolorize and adsorb for 1 hour, then filter. Concentrate the filtrate to a thick state under negative pressure at -0.09 MPa, cool to below 10°C for crystallization, filter, and dry at 80°C for 6 hours to obtain 8.1 g of methylprednisolone; the mass ratio of the crude methylprednisolone to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone to solvent 5 (dichloromethane and methanol) is 1:8.

[0210] The methylprednisolone obtained in Example 4 was tested using a Shimadzu LC-2030CPlus high performance liquid chromatograph, and the obtained liquid chromatogram is as Figure 4 shown, and the test data are shown in Table 4. It can be seen from Figure 4 and Table 4 that the purity of methylprednisolone in Example 4 is 99.921%;

[0211] Table 4 Liquid chromatographic test data of methylprednisolone prepared in Example 4

[0212]

[0213] The yield of methylprednisolone obtained in Example 4 is 58.6%.

[0214] Example 5

[0215] A method for preparing methylprednisolone:

[0216] (1) 10 g of cortisone acetate (24.9 mmol), 100 g of tetrahydrofuran, 2 g of ethanol, 6 g of triethyl orthoformate, and 0.015 g of p-toluenesulfonic acid were mixed and stirred at 35 °C for 2 hours for etherification reaction. TLC detection was carried out to confirm the completion of the reaction. Then, 3.0 g of N-methylaniline (28.0 mmol) and 0.9 g of aqueous formaldehyde solution (30.0 mmol) were added and stirred at 35 °C for 4 hours for Mannich reaction. TLC detection was carried out to confirm the completion of the reaction. Then, 10 wt% sulfuric acid was added to adjust the pH of the mixture to 2 for decomposition reaction. Then, it was concentrated under negative pressure to a thick state at -0.09 MPa, 50 ml of water was added and stirred for 1 hour for crystallization, filtered, washed with water until neutral, and dried at 80 °C for 6 hours to obtain 10.1 g of methylene compound; the mass ratio of cortisone acetate, solvent 1 (tetrahydrofuran), etherifying agent (ethanol), dehydrating agent (triethyl orthoformate), and catalyst 1 (p-toluenesulfonic acid) is 1:10:0.2:0.6:0.0015; the molar ratio of cortisone acetate, organic secondary amine (N-methylaniline), and aldehyde (formaldehyde) is 1:1.12:1.2;

[0217] (2) 10 g (24.2 mmol) of the methylene compound obtained in the step (1), 40 g of dichloromethane, 20 g of methanol, 0.5 g of 10% palladium on carbon by mass of palladium, 0.1 g of p-toluenesulfonic acid (0.58 mmol), and 0.04 g of hydrogen (100 mmol) were mixed and stirred at 20 °C for 6 hours for hydrogenation reaction. TLC detection was carried out to confirm the completion of the reaction. Then, it was filtered to remove palladium on carbon, and the filtrate was concentrated under negative pressure to a thick state at -0.09 MPa, 50 ml of water was added and stirred for 1 hour for crystallization, filtered, washed with water until neutral, and dried at 80 °C for 6 hours to obtain 9.6 g of 6a-methyl compound; the mass ratio of the methylene compound, solvent 2 (dichloromethane and methanol), and catalyst 2 (10% palladium on carbon by mass of palladium) is 1:6:0.05; the molar ratio of the methylene compound, catalyst 3 (p-toluenesulfonic acid), and hydrogen donor (hydrogen) is 1:0.024:1.65;

[0218] (3) Take 10 g (24.0 mmol) of the 6a-methyl compound obtained in step (2), 150 g of methylcyclohexane, 0.05 g of TFA (trifluoroacetic acid, 0.44 mmol), and 6.0 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone, 26.4 mmol), mix them, stir at 50 °C for 5 hours for the oxidation reaction, perform TLC detection, confirm that the reaction is complete, add 20 ml of 10% aqueous sodium bisulfite solution, then filter to remove hydroquinone, separate the aqueous layer, wash with 20 ml of 10% aqueous sodium bisulfite solution once again, separate the aqueous layer, concentrate the organic layer under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for crystallization for 1 hour, filter, wash with water until neutral, and dry at 80 °C for 6 hours to obtain 9.0 g of 1,2-dehydro compound; the mass ratio of the 6a-methyl compound to solvent 3 (methylcyclohexane) is 1:15; the molar ratio of the 6a-methyl compound, catalyst 4 (TFA), and oxidant (DDQ) is 1:0.018:1.1;

[0219] (4) Take 10 g (24.2 mmol) of the 1,2-dehydro compound obtained in step (3), 40 g of chloroform, 10 g of ethanol, and 0.3 g of calcium chloride (2.7 mmol), cool down to -30 °C, add 1.2 g of sodium borohydride (31.6 mmol) in 6 portions, stir for 2 hours for the reduction reaction, perform TLC detection, confirm that the reaction is complete, then add 50% aqueous acetic acid solution to adjust the pH to 6, concentrate under negative pressure at -0.09 MPa to a thick state, add 50 ml of water, stir for crystallization for 1 hour, filter, wash with water until neutral, and dry at 70 °C for 6 hours to obtain crude methylprednisolone acetate; the mass ratio of the 1,2-dehydro compound to solvent 4 (chloroform and ethanol) is 1:8; the molar ratio of the 1,2-dehydro compound, catalyst 5 (calcium chloride), and reducing agent (sodium borohydride) is 1:0.11:1.31;

[0220] (5) Add 10 g of methanol to all of the crude methylprednisolone acetate obtained in step (4), stir at 25 °C for 1 hour, filter, add the filter cake to 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon, reflux for decolorization and adsorption for 1 hour, then filter, concentrate the filtrate under negative pressure at -0.09 MPa to a thick state, cool down to below 10 °C for crystallization, after filtration, recrystallize the filter cake with dichloromethanol once again, and dry at 70 °C for 6 hours to obtain 8.3 g of high-quality methylprednisolone acetate; the mass ratio of the crude methylprednisolone acetate to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone acetate to solvent 4 (dichloromethane and methanol) is 1:8;

[0221] (6) Take 10 g (24.0 mmol) of the methylprednisolone acetate fine product obtained in step (5), 50 g of chloroform, and 20 g of ethanol. Under nitrogen protection, cool the mixture to -20°C, and dropwise add 10 g of a methanol solution of 0.05% potassium hydroxide and 10 g of an aqueous solution of 0.01% potassium carbonate. Hydrolyze at -20°C for 2 hours, perform TLC detection, confirm that the reaction is complete, add 50% acetic acid aqueous solution to adjust the pH to 6, concentrate under negative pressure to a thick state at -0.09 MPa, add 50 ml of water, stir and crystallize for 1 hour, filter, and wash with water until neutral to obtain the crude methylprednisolone; the mass ratio of the methylprednisolone acetate fine product to solvent 5 (chloroform and ethanol) is 1:12; the mass ratio of the methylprednisolone acetate fine product to the alkali solution is 1:2;

[0222] (7) Add 6 g of methanol to all of the crude methylprednisolone obtained in step (6), stir at 25 - 35°C for 1 hour, filter, add 50 g of dichloromethane, 30 g of methanol, and 1 g of activated carbon to the filter cake, reflux and decolorize and adsorb for 1 hour, then filter. Concentrate the filtrate to a thick state under negative pressure at -0.09 MPa, cool to below 10°C to crystallize, filter, and dry at 70°C for 6 hours to obtain 8.1 g of methylprednisolone; the mass ratio of the crude methylprednisolone to the activated carbon is 1:0.01; the mass ratio of the crude methylprednisolone to solvent 5 (dichloromethane and methanol) is 1:8.

[0223] The methylprednisolone obtained in Example 5 was tested using a Shimadzu LC-2030CPlus high-performance liquid chromatograph, and the obtained liquid chromatogram is as Figure 5 shown, and the test data are shown in Table 5. It can be seen from Figure 5 Table 5 that the purity of methylprednisolone in Example 5 is 99.902%;

[0224] Table 5 Liquid chromatographic test data of methylprednisolone prepared in Example 5

[0225]

[0226] The yield of methylprednisolone obtained in Example 5 is 58.7%.

[0227] It can be seen from the results of Examples 1 - 5 that the total yield of methylprednisolone prepared by the preparation method provided by the present invention is above 59.6%, and the purity is above 99.5%, having a high yield and high purity.

[0228] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing methylprednisolone, comprising the following steps: (1) cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 are mixed to carry out etherification reaction, then organic secondary amine and aldehyde are added to carry out Mannich reaction, and then acid is added to carry out decomposition reaction to obtain methylene product; (2) mixing the methylene compound obtained in step (1), solvent 2, catalyst 2, catalyst 3 and a hydrogen donor to carry out a hydrogenation reaction to obtain a methyl compound 6a; the hydrogen donor is hydrogen, ammonium formate, boric acid or formic acid; (3) mixing the 6a methyl compound obtained in step (2), solvent 3, catalyst 4 and oxidant for oxidation reaction to obtain 1,2 dehydrogenated product; the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone; the catalyst 4 is trifluoroacetic acid, N,O-bis(trimethylsilyl)acetamide or trimethylchlorosilane; (4) mixing the 1,2 dehydrogenated product obtained in step (3), solvent 4, catalyst 5 and reducing agent for reduction reaction to obtain crude methylprednisolone acetate; the catalyst 5 is calcium chloride, magnesium chloride, zinc chloride or barium chloride; the reduction reaction temperature is -40 to -30°C; (5) mixing the crude methylprednisolone acetate obtained in step (4), solvent 4 and an adsorbent for adsorption, and then sequentially performing crystallization and recrystallization to obtain a refined methylprednisolone acetate; (6) mixing the methylprednisolone acetate product obtained in step (5), solvent 5 and an alkaline solution to carry out a hydrolysis reaction to obtain a crude methylprednisolone product; (7) The crude methylprednisolone obtained in step (6), solvent 5 and an adsorbent are mixed for adsorption and then crystallization to obtain methylprednisolone.

2. The preparation method according to claim 1, characterized in that: In the step (1), the mass ratio of cortisone acetate, solvent 1, etherifying agent, dehydrating agent and catalyst 1 is 1: (3-20): (0.1-1): (0.5-1): (0.001-0.005); The molar ratio of cortisone acetate, organic secondary amine and aldehyde is 1:(1-2):(1-2); The solvent 1 is methanol, ethanol, tetrahydrofuran or acetic acid; The etherifying agent is methanol or ethanol; The dehydrating agent is triethyl orthoformate, trimethyl orthoformate, trimethyl orthoacetate or triethyl orthoacetate; The catalyst 1 is sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or methanesulfonic acid; The organic secondary amine is dimethylamine, diethylamine, N-methylaniline or piperidine; The aldehyde is formaldehyde, trioxymethylene or polyoxymethylene.

3. The preparation method according to claim 1, characterized in that: In the step (2), the mass ratio of the methylene compound, the solvent 2 and the catalyst 2 is 1: (3-10): (0.02-0.1); the molar ratio of the methylene compound, the catalyst 3 and the hydrogen donor is 1: (0.01-0.05): (1-2); The solvent 2 is a mixed solvent of solvent A and solvent B; the solvent A is dichloromethane or chloroform; the solvent B is tetrahydrofuran, methanol, ethanol or acetonitrile; The catalyst 2 is palladium carbon, PtO2 or Pd(OAc)2 with a palladium mass percentage of 3 to 10%; The catalyst 3 is p-toluenesulfonic acid, sulfuric acid, perchloric acid or methanesulfonic acid.

4. The preparation method according to claim 1 or 3, characterized in that: The temperature of the hydrogenation reaction in step (2) is 5 to 35°C.

5. The preparation method according to claim 1, characterized in that: In the step (3), the mass ratio of 6a methyl compound to solvent 3 is 1:(5-20); The molar ratio of 6a methyl compound, catalyst 4 and oxidant is 1:(0.01-0.05):(1-1.5); The solvent 3 is tetrahydrofuran, ethyl acetate, toluene, dioxane or methylcyclohexane.

6. The preparation method according to claim 1 or 5, characterized in that: The temperature of the oxidation reaction in step (3) is 0 to 65°C.

7. The preparation method according to claim 1, characterized in that: In the step (4), the mass ratio of 1,2 dehydrogenated product to solvent 4 is 1:(5-20); 1,2 The molar ratio of the dehydrogenated product, the catalyst 5 and the reducing agent is 1:(0.1-0.5):(1-2); The solvent 4 is a mixed solvent of solvent A and solvent C; the solvent A is dichloromethane or chloroform; the solvent C is methanol or ethanol; The reducing agent is potassium borohydride or sodium borohydride.

8. The preparation method according to claim 1, characterized in that: In the step (5), the adsorbent is activated carbon or neutral alumina; The mass ratio of the crude methylprednisolone acetate to the activated carbon is 1:(0.01-0.05); The mass ratio of the crude methylprednisolone acetate to the neutral alumina is 1:(0.1-0.5).

9. The preparation method according to claim 1, characterized in that: In the step (6), the mass ratio of methylprednisolone acetate fine product to solvent 5 is 1:(5-20); The mass ratio of methylprednisolone acetate fine product to alkaline solution is 1:(0.5-2); The solvent 5 is a mixed solvent of solvent A and solvent C; the solvent A is dichloromethane or chloroform; the solvent C is methanol or ethanol; The alkaline solution is a mixture of solution D and solution E; the solution D is a methanol / ethanol solution of sodium hydroxide / potassium hydroxide; the solution E is an aqueous solution of potassium carbonate / sodium carbonate; The concentration of the solution D is 0.05 wt %; the concentration of the solution E is 0.01 wt %.

10. The preparation method according to claim 1 or 9, characterized in that: The temperature of the hydrolysis reaction in step (6) is -20 to 0°C.

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