A process and apparatus for the preparation of 11 beta-hydroxy-pregna-1,4,16-trien-3,20-dione-21-acetate

Abstract

The application belongs to the technical field of organic matter synthesis, and particularly relates to a preparation method of 11beta-hydroxyl-pregn-1, 4, 16-triene-3, 20-dione-21-acetate. The application takes prednisone acetate as raw material, and realizes clean production of 11beta-hydroxyl-pregn-1, 4, 16-triene-3, 20-dione-21-acetate through three-step chemical reactions of esterification, reduction and elimination by adopting specific catalysts, reaction conditions, post-treatment methods and other process conditions. The three-step chemical reactions of the application are all carried out at catalysts and lower temperatures, so that larger impurities are avoided, the reaction liquid is directly subjected to the next operation after simple treatment, the production efficiency, reaction yield and product purity are effectively improved, and the application has important industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method and apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate. Background Technology

[0002] 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate (chemical formula below) is a key intermediate in the synthesis of sinet drugs such as glucocorticoids budesonide, ccyclosone, and desosonide. CAS No.: 3044-42-6.

[0003]

[0004] Currently, there are two main routes for the synthesis of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate: one is to obtain it from prednisolone through four chemical reactions: cyclic esterification, hydrolysis, esterification, and elimination.

[0005] Route 1

[0006] Another method involves the chemical synthesis of prednisolone acetate through three steps: esterification, reduction, and elimination.

[0007] Route 2.

[0008] The two processes mentioned above generate a large amount of wastewater, waste liquid, and waste residue. Route 1 involves cyclic esterification, hydrolysis, and esterification reactions, while Route 2 involves esterification and elimination reactions, with intermediate products precipitated by water precipitation. These processes generate a large amount of wastewater. In Route 2, some intermediate products (intermediate I and intermediate II) also need to be purified with solvents (dichloromethane, acetone, and ethyl acetate) to remove impurities generated during the reaction, resulting in a large amount of waste liquid and waste residue. This is not conducive to clean production and also results in low yield and purity. Summary of the Invention

[0009] To address the problems existing in the prior art, the present invention provides a method and apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate. The preparation method provided by the present invention not only achieves clean production but also improves reaction yield and product purity.

[0010] This invention provides a method for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate, comprising the following steps:

[0011] Prednisolone acetate, acetic anhydride, esterification catalyst, and methane chloride solvent are mixed in an esterification reactor and subjected to an esterification reaction to obtain an esterification reaction solution. The esterification catalyst includes a nitrogen-containing catalyst and a sulfur-containing catalyst. The nitrogen-containing catalyst includes one or more of pyridine, triethylamine, and ethylenediamine. The sulfur-containing catalyst includes one or more of p-toluenesulfonic acid, 2-sulfuric acid, and concentrated sulfuric acid.

[0012] The esterification reaction solution is pumped into the first esterification reaction post-treatment vessel, and then subjected to the first washing and standing separation in sequence. The resulting first esterified organic phase is pumped into the second esterification reaction post-treatment vessel, and then subjected to the removal of impurities by a weak alkaline solution and standing separation in sequence. The resulting second esterified organic phase is dried with a drying agent to obtain a solution of intermediate I.

[0013] The solution of intermediate I, the nucleophilic reducing agent, the reduction catalyst, and the alcohol solvent are mixed in a reduction reactor and then subjected to a reduction reaction in sequence under a protective atmosphere. The mixture is purified with a weak acid solution and allowed to stand for separation. The resulting reduced organic layer is pumped into a reduction reaction treatment reactor and subjected to a second washing and standing for separation to obtain a solution of intermediate II. The reduction catalyst includes calcium chloride and / or magnesium chloride.

[0014] The solution of intermediate II was pumped into an elimination reaction vessel for concentration, and then mixed with an alcohol solvent, elimination catalyst and KOAc. The elimination reaction, concentration, extraction and static separation were carried out in sequence to obtain the elimination reaction organic layer.

[0015] The elimination reaction organic layer was pumped into an elimination reaction treatment vessel, washed and allowed to stand for layering. The resulting organic phase was then pumped into the elimination reaction vessel for concentration and crystallization to obtain 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate. The crystallization reagent was an alcohol solvent.

[0016] Intermediate I; Intermediate II.

[0017] Preferably, the mass ratio of the nitrogen-containing catalyst to the sulfur-containing catalyst is 0.02~0.1:0.1~0.5; the mass ratio of prednisolone acetate to acetic anhydride is 1:0.5~1; and the mass ratio of prednisolone acetate to the nitrogen-containing catalyst is 1:0.02~0.1.

[0018] Preferably, the methane chloride solvent includes dichloromethane and / or trichloromethane; the mass ratio of prednisolone acetate to the methane chloride solvent is 1:0.5~1; the esterification reaction is carried out at a temperature of 25~35℃ for 6~8 hours.

[0019] Preferably, the weakly alkaline solution comprises an aqueous solution of NaHCO3; the mass concentration of the NaHCO3 aqueous solution is 10%; the purification of the impurity with the weakly alkaline solution is achieved by adjusting the pH value of the first esterified organic phase to 6-6.5 using the weakly alkaline solution.

[0020] Preferably, the alcohol solvent in the elimination reaction, reduction reaction, and crystallization is one or more of methanol, ethanol, and tert-butanol; the nucleophilic reducing agent includes NaBH4;

[0021] The reduction reaction is carried out at a temperature of -45 to -40°C for 0.8 to 1.2 hours.

[0022] Preferably, the elimination catalyst includes one or more of acetic acid, formic acid and oxalic acid; the elimination reaction temperature is 65~85℃ and the holding time is 4~6h.

[0023] Preferably, the weak acid solution comprises an aqueous HOAc solution with a mass concentration of 30%.

[0024] Preferably, the crystallization temperature is 0~10℃ and the time is 0.8~1.2h.

[0025] Preferably, after crystallization, the solid obtained after crystallization is dried at a temperature of 70-80°C for 5-8 hours.

[0026] The present invention also provides an apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate, comprising an esterification reactor 1;

[0027] The first esterification reaction post-treatment vessel 2 is connected to the esterification reactor via a pipeline;

[0028] A second esterification reaction post-treatment vessel 3 is connected to the first esterification reaction post-treatment vessel 1 via a pipeline;

[0029] The reduction reactor 4 is connected to the first esterification reaction post-treatment reactor 2 via a pipeline;

[0030] Reduction reaction treatment vessel 5 is connected to the reduction reaction vessel via a pipeline;

[0031] Elimination reactor 3 is connected to the reduction reaction treatment vessel via a pipeline;

[0032] Elimination reaction treatment vessel 7 is connected to the elimination reaction vessel via a pipeline.

[0033] This invention provides a method for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate, comprising the following steps: mixing prednisolone acetate, acetic anhydride, an esterification catalyst, and a methane chloride solvent in an esterification reactor, and then carrying out an esterification reaction to obtain an esterification reaction solution; the esterification catalyst includes a nitrogen-containing catalyst and a sulfur-containing catalyst; the nitrogen-containing catalyst includes one or more of pyridine, triethylamine, and ethylenediamine; the sulfur-containing catalyst includes one or more of p-toluenesulfonic acid, 2-sulfuric acid, and concentrated sulfuric acid; and pumping the esterification reaction solution into a post-esterification reaction treatment. The first esterified organic phase is sequentially washed and allowed to stand for layering in a reactor. The resulting first esterified organic phase is pumped into a second esterification reaction post-treatment reactor, where it is sequentially purified with a weakly alkaline solution and allowed to stand for layering. The resulting second esterified organic phase is dried with a desiccant to obtain a solution of intermediate I. The solution of intermediate I, a nucleophilic reducing agent, a reduction catalyst, and an alcohol solvent are mixed in a reduction reactor and then subjected to a reduction reaction sequentially under a protective atmosphere. The mixture is purified with a weakly acidic solution and allowed to stand for layering. The resulting reduced organic layer is pumped into a reduction reaction treatment reactor and sequentially washed and allowed to stand for layering to obtain a solution of intermediate II. The reduction catalyst includes calcium chloride and / or magnesium chloride.

[0034] The solution of intermediate II is pumped into an elimination reaction vessel for concentration, then mixed with an alcohol solvent, elimination catalyst, and KOAc. The mixture undergoes elimination reaction, concentration, extraction, and settling to separate the layers, yielding an elimination reaction organic layer. This organic layer is then pumped into an elimination reaction treatment vessel for washing and settling to separate the layers. The resulting organic phase is pumped into the elimination reaction vessel for concentration and crystallization, yielding 11β-hydroxy-pregnazine-1,4,16-triene-3,20-dione-21-acetate. The crystallization reagent is an alcohol solvent. This invention uses prednisolone acetate as a raw material and, through a three-step chemical reaction involving esterification, reduction, and elimination, employs specific catalysts, reaction conditions, and post-treatment methods to achieve the clean production of 11β-hydroxy-pregnazine-1,4,16-triene-3,20-dione-21-acetate. The three-step chemical reaction solution of this invention, after simple treatment, can be directly used in the next step, effectively improving the reaction yield and product purity, and has significant industrial application prospects. Attached Figure Description

[0035] Figure 1 This is a schematic diagram of an apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate, where 1 is an esterification reactor, 2 is a first esterification reaction post-treatment reactor, 3 is a second esterification reaction post-treatment reactor, 4 is a reduction reactor, 5 is an elimination reactor, and 7 is an elimination reaction treatment reactor.

[0036] Figure 2The HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 1 is shown.

[0037] Figure 3 The HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 2 is shown.

[0038] Figure 4 The HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 3 is shown.

[0039] Figure 5 The HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 4 is shown.

[0040] Figure 6 The image shows the HPLC detection chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 5. Detailed Implementation

[0041] This invention provides a method for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate, comprising the following steps:

[0042] Prednisolone acetate, acetic anhydride, esterification catalyst, and methane chloride solvent are mixed in an esterification reactor and then subjected to an esterification reaction to obtain an esterification reaction solution. The esterification catalyst includes a nitrogen-containing catalyst and a sulfur-containing catalyst. The nitrogen-containing catalyst includes one or more of pyridine, triethylamine, and ethylenediamine. The sulfur-containing catalyst includes one or more of p-toluenesulfonic acid, 2-sulfuric acid, and concentrated sulfuric acid.

[0043] The esterification reaction solution is pumped into the first esterification reaction post-treatment vessel, and then subjected to first washing and standing for layering. The resulting first esterified organic phase is pumped into the second esterification reaction post-treatment vessel, and then subjected to impurity removal by a weak alkaline solution and standing for layering. The resulting second esterified organic phase is dried with a drying agent to obtain a solution of intermediate I.

[0044] The solution of intermediate I, the nucleophilic reducing agent, the reduction catalyst, and the alcohol solvent are mixed in a reduction reactor and then subjected to a reduction reaction in sequence under a protective atmosphere. The mixture is purified with a weak acid solution and allowed to stand for separation. The resulting reduced organic layer is pumped into a reduction reaction treatment reactor and subjected to a second washing and standing for separation to obtain a solution of intermediate II. The reduction catalyst includes calcium chloride and / or magnesium chloride.

[0045] The solution of intermediate II was pumped into an elimination reaction vessel for concentration, and then mixed with alcohol solvent, elimination catalyst and KOAc. The elimination reaction, concentration, extraction and static separation were carried out in sequence to obtain the elimination reaction organic layer.

[0046] The elimination reaction organic layer was pumped into an elimination reaction treatment vessel, washed and allowed to stand for layering, and the resulting organic phase was pumped into an elimination reaction vessel for concentration and crystallization to obtain 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate; the crystallization reagent was an alcohol solvent.

[0047] Intermediate I;

[0048] Intermediate II.

[0049] In this invention, prednisolone acetate, acetic anhydride, esterification catalyst and methane chloride solvent are mixed in an esterification reactor and then subjected to an esterification reaction to obtain an esterification reaction solution.

[0050] In this invention, the methane chloride solvent includes dichloromethane and / or trichloromethane, more preferably dichloromethane. In this invention, the esterification catalyst includes a nitrogen-containing catalyst and a sulfur-containing catalyst; the nitrogen-containing catalyst includes one or more of pyridine, triethylamine, and ethylenediamine, more preferably triethylamine; the sulfur-containing catalyst includes one or more of p-toluenesulfonic acid, 2-sulfuric acid, and concentrated sulfuric acid, more preferably concentrated sulfuric acid. In this invention, the mass ratio of the nitrogen-containing catalyst to the sulfur-containing catalyst is preferably 0.02~0.1:0.1~0.5, more preferably 0.05~0.06:0.2~0.4.

[0051] In this invention, the mass ratio of prednisolone acetate to acetic anhydride is preferably 1:0.5~1, more preferably 1:0.7~0.8. In this invention, the mass ratio of prednisolone acetate to the methane chloride solvent is preferably 1:1.5~3, more preferably 1:2~2.5. In this invention, the mass ratio of prednisolone acetate to the nitrogen-containing catalyst is preferably 1:0.02~0.1, more preferably 1:0.05~0.06.

[0052] In this invention, the mixing is preferably carried out by first pumping methane chloride solvent, acetic anhydride and nitrogen-containing catalyst into the esterification reactor for a first mixing, and then adding sulfur-containing catalyst and prednisolone acetate into the esterification reactor for a second mixing.

[0053] In this invention, the esterification reaction is preferably carried out under stirring conditions. The temperature of the esterification reaction is preferably 25-35°C, more preferably 30°C, and the holding time is preferably 6-8 hours, more preferably 7 hours.

[0054] After the esterification reaction, the present invention pumps the esterification reaction solution obtained from the esterification reaction into the first esterification reaction post-processing vessel, and performs the first washing and standing layering in sequence. The resulting first esterified organic phase is pumped into the second esterification reaction post-processing vessel, and is subjected to impurity removal by a weak alkaline solution and standing layering in sequence. The resulting second esterified organic phase is dried by a drying agent to obtain the solution of intermediate I.

[0055] In this invention, the mass ratio of water to prednisolone acetate is preferably 1 to 3:1, more preferably 2:1.

[0056] In this invention, the reagent for the first washing is preferably water; the washing is preferably carried out under stirring conditions; the washing temperature is preferably 20~30℃; and the washing time is preferably 2h.

[0057] In this invention, the weakly alkaline solution preferably comprises an aqueous solution of NaHCO3, and the mass concentration of the NaHCO3 aqueous solution is preferably 10%. In this invention, the removal of impurities with the weakly alkaline solution is preferably performed by adjusting the pH of the reduced organic layer to 6-6.5 using a weakly acidic solution. In this invention, the desiccant is preferably anhydrous sodium sulfate. In this invention, the mass ratio of the desiccant to prednisolone acetate is preferably 0.1-0.5:1, more preferably 0.2-0.3:1. In this invention, the drying is preferably carried out under stirring conditions. In this invention, the drying time is preferably 1 hour.

[0058] After obtaining the solution of intermediate I, the present invention mixes the solution of intermediate I, the nucleophilic reducing agent, the reduction catalyst and the alcohol solvent in a reduction reactor, and then carries out a reduction reaction in sequence under a protective atmosphere. The solution is purified by a weak acid solution and allowed to stand for separation. The resulting reduced organic layer is pumped into a reduction reaction treatment vessel and subjected to a second washing and standing for separation in sequence to obtain the solution of intermediate II.

[0059] In this invention, the reduction catalyst comprises calcium chloride and / or magnesium chloride, more preferably calcium chloride. In this invention, the nucleophilic reducing agent is preferably NaBH4. In this invention, the protective atmosphere is preferably nitrogen. In this invention, the mass ratio of prednisolone acetate to the nucleophilic reducing agent is preferably 1:0.15~0.20, more preferably 1:0.16~0.17. In this invention, the mass ratio of prednisolone acetate to the alcohol solvent is preferably 1:2~5, more preferably 1:3~4. In this invention, the mass ratio of prednisolone acetate to the reduction catalyst is preferably 1:0.005~0.2, more preferably 1:0.05~0.1.

[0060] In this invention, the temperature of the reduction reaction is preferably -45 to -40°C, more preferably -41 to -43°C, and the time is preferably 0.8 to 1.2 hours, more preferably 1 hour.

[0061] In this invention, the weak acid solution preferably comprises an aqueous solution of HOAc, and the mass concentration of the HOAc aqueous solution is preferably 30%. In this invention, the removal of impurities with the weak alkaline solution is preferably performed by adjusting the pH of the reduced organic layer to 6-6.5 using a weak acidic solution. In this invention, the reagent for the second washing is preferably an aqueous solution of 10 wt% NaCl; the washing is preferably carried out under stirring conditions. In this invention, the concentration is preferably negative pressure concentration, the concentration temperature is preferably 35-60°C, more preferably 40-50°C, and the concentration pressure is preferably -0.06 to -0.09 MPa, more preferably -0.06 to -0.09 MPa.

[0062] After obtaining the solution of intermediate II, the solution of intermediate II of the present invention is pumped into an elimination reaction vessel for concentration, and then mixed with alcohol solvent, elimination catalyst and KOAc, and the elimination reaction, concentration, methane chloride redissolution, third washing and standing to separate layers are carried out in sequence to obtain the elimination reaction organic layer.

[0063] In this invention, the concentration is preferably concentrated to near dryness. In this invention, the methane chloride solvent obtained after concentration is preferably recycled. In this invention, the alcohol solvent preferably includes one or more of methanol, ethanol, and tert-butanol, more preferably ethanol. In this invention, the elimination catalyst preferably includes one or more of acetic acid, formic acid, and oxalic acid, more preferably acetic acid. In this invention, the mass ratio of prednisolone acetate to KOAc is preferably 1:0.45~0.55, more preferably 1:0.5. In this invention, the mass ratio of prednisolone acetate to the alcohol solvent is preferably 1:5~10, more preferably 1:7~8. In this invention, the mass ratio of prednisolone acetate to the elimination catalyst is preferably 1:0.01~0.02, more preferably 1:0.015.

[0064] In this invention, the temperature of the elimination reaction is preferably 65~85℃, more preferably 70~80℃, and the holding time is preferably 4~6h, more preferably 5h.

[0065] In this invention, the methane chloride solvent is preferably a solvent obtained by concentrating the solution of intermediate II.

[0066] After obtaining the elimination reaction organic layer, the present invention pumps the elimination reaction organic layer into the elimination reaction treatment vessel, performs a fourth washing and static separation, and pumps the obtained organic phase into the elimination reaction vessel for concentration and crystallization to obtain 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate.

[0067] In this invention, the reagent for the fourth washing is preferably water, and the concentration is preferably concentrated to dryness. In this invention, the reagent for crystallization is an alcohol solvent. In this invention, the crystallization temperature is preferably 0~10℃, more preferably 4℃, and the time is preferably 0.8~1.2h, more preferably 1h. In this invention, the crystallization is preferably carried out under stirring conditions.

[0068] In this invention, after crystallization, the process preferably further includes filtration, washing, and drying of the crystallized system. In this invention, the filtration is preferably centrifugal filtration. In this invention, the drying temperature is preferably 70-80°C, more preferably 75°C, and the drying time is preferably 5-8 hours, more preferably 6 hours.

[0069] like Figure 1 As shown, the present invention also provides an apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate, comprising an esterification reactor 1;

[0070] The first esterification reaction post-treatment vessel 2 is connected to the esterification reaction vessel 1 via a pipeline;

[0071] The second esterification reaction post-treatment vessel 3 is connected to the first esterification reaction post-treatment vessel via a pipeline;

[0072] The reduction reactor 4 is connected to the first esterification reaction post-treatment reactor 2 via a pipeline;

[0073] The reduction reaction treatment vessel 5 is connected to the reduction reaction vessel 4 via a pipeline;

[0074] Elimination reaction vessel 6 is connected to reduction reaction vessel 5 via a pipeline;

[0075] Elimination reaction treatment vessel 7 is connected to the elimination reaction vessel via a pipeline.

[0076] In this invention, the apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate includes an esterification reactor 1.

[0077] In this invention, the bottom of the esterification reactor 1 is provided with an outlet. In this invention, the esterification reactor 1 is equipped with a digital display thermometer.

[0078] In this invention, the apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate includes a first post-esterification reaction treatment vessel 2 connected to an esterification reaction vessel 1 via a pipeline. In this invention, the bottom outlet of the esterification reaction vessel 1 is connected to the first post-esterification reaction treatment vessel 2 via a pipeline.

[0079] In this invention, the apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate includes a second esterification post-treatment vessel 3 connected to a first esterification post-treatment vessel via a pipeline. In this invention, the bottom outlet of the first esterification post-treatment vessel is connected to the second esterification post-treatment vessel 3 via a pipeline. In this invention, the second esterification post-treatment vessel 3 is equipped with a mixing tank, a dropping tank, and a pH controller.

[0080] In this invention, the apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate includes a reduction reactor 4 connected to a first esterification reaction post-treatment reactor 2 via a pipeline. In this invention, the bottom outlet of the first esterification reaction post-treatment reactor 2 is connected to the reduction reactor 4 via a pipeline.

[0081] In this invention, the apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate is connected to a reduction reaction vessel 5 via a pipeline to a reduction reaction vessel 4. In this invention, the bottom outlet of the reduction reaction vessel 4 is connected to the reduction reaction vessel 5 via a pipeline.

[0082] In this invention, the apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate includes an elimination reaction vessel 6 connected to a reduction reaction vessel 5 via a pipeline. In this invention, the bottom outlet of the reduction reaction vessel 5 is connected to the elimination reaction vessel 6 via a pipeline. In this invention, the elimination reaction vessel 6 is equipped with a condenser and a solvent receiving tank.

[0083] In this invention, the apparatus for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate includes an elimination reaction treatment vessel 7 connected to an elimination reaction vessel 6. In this invention, the bottom outlet of the elimination reaction vessel 6 is connected to the elimination reaction treatment vessel 7 via a pipe.

[0084] The production method of this invention uses fewer types of solvents, all of which can be recycled and reused; there is no water separation step, significantly reducing wastewater discharge; there is no drying process for intermediate products, significantly reducing energy consumption; materials are transferred within the reaction vessel and pipelines, avoiding contact with operators, and waste liquid is entrusted to a qualified company for harmless incineration treatment. Moreover, the preparation method provided by this invention has the advantages of simple operation, short production cycle, and green environmental protection.

[0085] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0086] Example 1

[0087] 300 kg of dichloromethane, 60 kg of acetic anhydride, and 5 kg of triethylamine were pumped into a 500 L esterification reactor using a diaphragm pump. Then, 100 kg of prednisolone acetate and 10 kg of p-toluenesulfonic acid were added. The mixture was heated to 35 °C with hot water and stirred for 6 hours. TLC analysis at the sampling port confirmed the completeness of the reaction. 200 kg of drinking water was added to the esterification reactor beforehand. The resulting esterification reaction solution was then transferred to esterification reactor 1 using a diaphragm pump. The mixture was kept at 30 °C and stirred for 2 hours, then allowed to stand and separate into layers.

[0088] The dichloromethane layer was transferred to esterification reaction vessel 2 via a diaphragm pump. While stirring, 10 wt.% NaHCO3 aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5, and the mixture was allowed to stand and separate into layers. The dichloromethane layer was then transferred to esterification reaction vessel 1 via a diaphragm pump, and 10 kg of anhydrous NaSO4 was added and stirred and dried for 1 hour to obtain a dichloromethane solution of intermediate I.

[0089] A dichloromethane solution of intermediate I and 200 kg of methanol were pumped into a 1000 L reduction reactor via a diaphragm pump. Then, 10 kg of calcium chloride was added. Under nitrogen protection, the mixture was cooled to -40 °C by purging with liquid nitrogen. Over 2 hours, 18 kg of NaBH4 was added in 6 portions, and the reduction reaction was carried out for 1 hour. TLC analysis at the sampling port confirmed the completeness of the reaction. Then, 30 wt% HOAc aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5, and the mixture was allowed to stand and separate into layers. The organic layer (lower layer) was transferred to a reduction reaction processing vessel via a diaphragm pump, and then 10 wt.% NaCl aqueous solution was added, followed by stirring and washing once. The mixture was then allowed to stand and separate into layers to obtain a dichloromethane solution of intermediate II.

[0090] The dichloromethane solution of intermediate II was transferred to an elimination reactor using a diaphragm pump. The solution was heated to 45°C with hot water and concentrated to near dryness under negative pressure to recover the solvent (dichloromethane). 600 kg of ethanol and 1 kg of acetic acid were pumped into the elimination reactor, followed by 50 kg of KOAc. The mixture was heated to 80°C with steam and stirred for 4 hours. A sample was taken for TLC analysis to confirm complete reaction. After concentrating to near dryness (ethanol recovery) with hot water under negative pressure at 80°C, the solution was cooled to 25°C, and 300 kg of recovered dichloromethane and 100 kg of drinking water were pumped in. The mixture was stirred, washed to remove salt, and allowed to settle for separation. The organic layer (lower layer) was transferred to an elimination reaction vessel using a diaphragm pump, and another 100 kg of drinking water was added. The mixture was stirred, washed once, and allowed to settle for separation.

[0091] The organic layer (lower layer) was transferred to the elimination reactor using a diaphragm pump. Hot water was heated to 45°C, and the mixture was concentrated to near dryness under negative pressure (to recover the solvent). Then, 100 kg of recovered ethanol was pumped in, followed by cooling to 4°C and stirring to induce crystallization for 1 hour. The precipitated material was transferred to a centrifuge for centrifugation and filtration. The reactor was washed with 10 kg of ethanol, and the filter cake was rinsed and dried. The filter cake was then transferred to a vacuum dryer and dried at 80°C for 6 hours to obtain 86.8 kg of a pale yellow, sandy solid, namely 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate.

[0092] In Example 1, the yield of the product 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate was 86.8% (based on the mass of prednisolone acetate), and the purity was 99.2% as determined by HPLC.

[0093] Figure 2 This is the HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 1. Figure 2 The information obtained is shown in Table 1.

[0094] Table 1 Figure 2 Information data

[0095]

[0096] Example 2

[0097] 150 kg of chloroform, 65 kg of acetic anhydride, and 2 kg of ethylenediamine were pumped into a 500 L esterification reactor using a diaphragm pump. Then, 100 kg of prednisolone acetate and 20 kg of concentrated sulfuric acid were added. The mixture was heated to 35 °C with hot water and stirred for 8 hours. TLC analysis at the sampling port confirmed the complete reaction. 200 kg of drinking water was added to esterification reactor 1 beforehand. The esterification reaction solution was then transferred to esterification reactor 1 via a diaphragm pump, kept at 20-30 °C with stirring for 2 hours, and allowed to separate into layers. The organic layer (lower layer) was transferred to esterification reactor 2 via a diaphragm pump. While stirring, 10 wt.% NaHCO3 aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5. The mixture was allowed to separate into layers again. The organic layer (lower layer) was transferred back to esterification reactor 1 via a diaphragm pump, and 10 kg of anhydrous NaSO4 was added and stirred and dried for 1 hour to obtain a dichloromethane solution of intermediate I.

[0098] A chloroform solution of intermediate I and 200 kg of ethanol were pumped into a 1000 L reduction reactor via a diaphragm pump. Then, 5 kg of magnesium chloride was added. Under nitrogen protection, the mixture was cooled to -45 °C by purging with liquid nitrogen. Over 2 hours, 18 kg of NaBH4 was added in 6 portions, and the reduction reaction was carried out for 1 hour. TLC analysis at the sampling port confirmed the completeness of the reaction. Then, 30 wt% HOAc aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5, and the mixture was allowed to stand and separate into layers. The organic layer (lower layer) was transferred to a reduction reaction processing vessel via a diaphragm pump, and then 10 wt.% NaCl aqueous solution was added, followed by stirring and washing once. The mixture was then allowed to stand and separate into layers to obtain a chloroform solution of intermediate II.

[0099] The chloroform solution of intermediate 3 was transferred to an elimination reactor using a diaphragm pump. Hot water was heated to 50°C, and the solution was concentrated to near dryness under negative pressure to recover chloroform. 500 kg of methanol and 1 kg of formic acid were pumped into the elimination reactor, followed by 50 kg of KOAc. The temperature was raised to 70°C by steam, and the reaction was stirred for 6 hours. A sample was taken for TLC analysis to confirm complete reaction. The solution was then concentrated to near dryness under negative pressure with hot water at 70°C to recover the solvent, methanol. The temperature was lowered to 30°C, and 200 kg of recovered chloroform and 100 kg of drinking water were pumped in. The mixture was stirred, washed to remove salt, and allowed to stand for separation. The organic layer (lower layer) was transferred to an elimination reaction vessel using a diaphragm pump, and 100 kg of drinking water was added. The mixture was stirred, washed once, and allowed to stand for separation. The organic layer (lower layer) was then transferred to the elimination reactor using a diaphragm pump, heated to 60°C with hot water, and concentrated to near dryness under negative pressure to recover the solvent, chloroform. Another 100 kg of recovered methanol was pumped in, the temperature was lowered to 4 °C, and the mixture was stirred to crystallize for 1 hour. The material was then transferred to a centrifuge for centrifugation and filtration. 5 kg of methanol was used to wash the reaction vessel and rinse the filter cake. The filter cake was then dried and transferred to a vacuum dryer at 75 °C for 6 hours to obtain 87.3 kg of a pale yellow, sandy solid (11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate).

[0100] In Example 2, the yield of the product 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate was 87.3% (based on the mass of prednisolone acetate), and the purity was 99.2% as determined by HPLC.

[0101] Figure 3 This is the HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 2. Figure 3 The information obtained is shown in Table 2.

[0102] Table 2 Figure 3 Information data

[0103]

[0104] Example 3

[0105] 300 kg of dichloromethane, 60 kg of acetic anhydride, and 5 kg of pyridine were pumped into a 500 L esterification reactor using a diaphragm pump. Then, 100 kg of prednisolone acetate and 15 kg of 2-sulfobenzoic acid were added. The mixture was heated to 35 °C and stirred for 8 hours. TLC analysis at the sampling port confirmed the complete reaction. 200 kg of drinking water was added to the esterification reactor beforehand. The esterification reaction solution was then transferred to the reactor using a diaphragm pump, kept at 20 °C, stirred for 2 hours, and allowed to separate into layers. The organic layer (lower layer) was transferred to the esterification reactor using a diaphragm pump. While stirring, 10 wt.% NaHCO3 aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5. The mixture was allowed to separate into layers again. The organic layer (lower layer) was transferred to the esterification reactor using a diaphragm pump, and 10 kg of anhydrous NaSO4 was added and stirred and dried for 1 hour to obtain a dichloromethane solution of intermediate I.

[0106] A dichloromethane solution of intermediate I and 200 kg of methanol were pumped into a 1000 L reduction reactor via a diaphragm pump. Then, 10 kg of calcium chloride was added. Under nitrogen protection, the mixture was cooled to -40 °C by purging with liquid nitrogen. Over 2 hours, 18 kg of NaBH4 was added in 6 portions, and the reduction reaction was carried out for 1 hour. TLC analysis at the sampling port confirmed the completeness of the reaction. Then, 30 wt% HOAc aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5, and the mixture was allowed to stand and separate into layers. The organic layer (lower layer) was transferred to a reduction reaction processing vessel via a diaphragm pump, and then 10 wt.% NaCl aqueous solution was added, followed by stirring and washing once. The mixture was then allowed to stand and separate into layers to obtain a dichloromethane solution of intermediate II.

[0107] The dichloromethane solution of intermediate II was transferred to an elimination reactor using a diaphragm pump. Hot water was heated to 35°C, and the solution was concentrated to near dryness under negative pressure to recover dichloromethane. 500 kg of tert-butanol and 2 kg of oxalic acid were pumped into the elimination reactor, followed by 50 kg of KOAc. The temperature was raised to 75°C by steam, and the reaction was stirred for 5 hours. A sample was taken for TLC analysis to confirm complete reaction. The solution was then concentrated to near dryness under negative pressure with hot water at 80°C to recover the solvent tert-butanol. The temperature was lowered to 25°C, and 300 kg of recovered dichloromethane and 100 kg of drinking water were pumped in. The mixture was stirred, washed to remove salt, and allowed to stand for separation. The organic layer (lower layer) was transferred to an elimination treatment vessel using a diaphragm pump, and 100 kg of drinking water was added. The mixture was stirred, washed once, and allowed to stand for separation. The organic layer (lower layer) was then transferred to an elimination reactor using a diaphragm pump. Hot water was heated to 40°C, and the solution was concentrated to near dryness under negative pressure to recover the solvent (dichloromethane), which could be reused. 100 kg of methanol was pumped in, the temperature was lowered to 4 °C, and the mixture was stirred to crystallize for 1 hour. The precipitated material was transferred to a centrifuge for centrifugation and filtration. 10 kg of methanol was used to wash the reaction vessel and rinse the filter cake. The filter cake was then dried and transferred to a vacuum dryer at 75 °C for 6 hours to obtain 88.5 kg of a pale yellow, sandy solid (11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate).

[0108] In Example 3, the yield of the product 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate was 88.5% (based on the mass of prednisolone acetate), and the purity was 99.0% as determined by HPLC.

[0109] Figure 4 This is the HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 3. Figure 4 The information obtained is shown in Table 3.

[0110] Table 3 Figure 4 Information data

[0111]

[0112] Example 4

[0113] 200 kg of chloroform, 65 kg of acetic anhydride, and 2 kg of ethylenediamine were pumped into a 500 L esterification reactor using a diaphragm pump. Then, 100 kg of prednisolone acetate and 20 kg of p-toluenesulfonic acid were added. The mixture was heated to 30 °C with hot water and stirred for 6 hours. TLC analysis at the sampling port confirmed the complete reaction. 200 kg of drinking water was added to the esterification reactor beforehand. The esterification reaction solution was then transferred to esterification reactor 1 via a diaphragm pump, kept at 20 °C with stirring for 2 hours, and allowed to separate into layers. The organic layer (lower layer) was transferred to the esterification reactor via a diaphragm pump. While stirring, 10 wt.% NaHCO3 aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5. The mixture was allowed to separate into layers again. The organic layer (lower layer) was transferred to the esterification reactor via a diaphragm pump, and 10 kg of anhydrous NaSO4 was added and stirred and dried for 1 hour to obtain a dichloromethane solution of intermediate I.

[0114] A chloroform solution of intermediate I and 200 kg of methanol were pumped into a 1000 L reduction reactor via a diaphragm pump. Then, 5 kg of magnesium chloride was added. Under nitrogen protection, the mixture was cooled to -40 °C by purging with liquid nitrogen. Over 2 hours, 18 kg of NaBH3 was added in 6 portions, and the reduction reaction was carried out for 1 hour. TLC analysis at the sampling port confirmed the completeness of the reaction. Then, 30 wt% HOAc aqueous solution was added dropwise using an online pH controller to adjust the pH to 6, and the mixture was allowed to stand and separate into layers. The organic layer (lower layer) was transferred to a reduction reaction processing vessel via a diaphragm pump, and then 10 wt% NaCl aqueous solution was added, followed by stirring and washing once. The mixture was then allowed to stand and separate into layers to obtain a chloroform solution of intermediate II.

[0115] The chloroform solution of intermediate II was transferred to an elimination reactor using a diaphragm pump. Hot water was heated to 60°C, and the solution was concentrated to near dryness under negative pressure to recover the solvent, chloroform. 500 kg of methanol and 1 kg of formic acid were pumped into the elimination reactor, followed by 50 kg of KOAc. The temperature was raised to 65°C by steam, and the reaction was stirred for 6 hours. A sample was taken for TLC analysis to confirm complete reaction. The solution was then concentrated to near dryness under negative pressure with hot water at 60°C to recover the solvent, methanol. The temperature was lowered to 25°C, and 200 kg of recovered chloroform and 100 kg of drinking water were pumped in. The mixture was stirred, washed to remove salt, and allowed to stand for separation. The organic layer (lower layer) was transferred to an elimination reaction vessel using a diaphragm pump, and 100 kg of drinking water was added. The mixture was stirred, washed once, and allowed to stand for separation. The organic layer (lower layer) was then transferred to an elimination reactor using a diaphragm pump, and hot water was heated to 50°C. The solution was concentrated to near dryness under negative pressure to recover the solvent, chloroform. 80 kg of recovered methanol was pumped in, the temperature was lowered to 4 °C, and the mixture was stirred to crystallize for 1 hour. The precipitated material was transferred to a centrifuge for centrifugation and filtration. 5 kg of methanol was used to wash the reaction vessel and rinse the filter cake. The filter cake was then dried and transferred to a vacuum dryer at 80 °C for 6 hours to obtain 89.3 kg of a pale yellow, sandy solid (11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate).

[0116] In Example 4, the yield of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate was 89.3% (based on the mass of prednisolone acetate), and the purity was 99.1% as determined by HPLC.

[0117] Figure 5 This is the HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 4. Figure 5 The information obtained is shown in Table 4.

[0118] Table 4 Figure 5 Information data

[0119]

[0120] Example 5

[0121] 300 kg of dichloromethane, 65 kg of acetic anhydride, and 5 kg of ethylenediamine were pumped into a 500 L esterification reactor using a diaphragm pump. Then, 100 kg of prednisolone acetate and 10 kg of p-toluenesulfonic acid were added. The mixture was heated to 35 °C and stirred for 8 hours. TLC analysis at the sampling port confirmed the complete reaction. 200 kg of drinking water was added to the esterification reactor beforehand. The esterification reaction solution was then transferred to the esterification reactor using a diaphragm pump, kept at 30 °C, stirred for 2 hours, and allowed to separate into layers. The organic layer (lower layer) was transferred to esterification reactor 2 using a diaphragm pump. While stirring, 10 wt% NaHCO3 aqueous solution was added dropwise using an online pH controller to adjust the pH to 6.5. The mixture was allowed to separate into layers again. The organic layer (lower layer) was transferred to the esterification reactor using a diaphragm pump, and 10 kg of anhydrous NaSO4 was added and stirred and dried for 1 hour to obtain a dichloromethane solution of intermediate I.

[0122] A dichloromethane solution of intermediate I and 300 kg of ethanol were pumped into a 1000 L reduction reactor via a diaphragm pump. Then, 10 kg of calcium chloride was added. Under nitrogen protection, the mixture was cooled to -40 °C by purging with liquid nitrogen. Over 2 hours, 18 kg of NaBH4 was added in 6 portions, and the reduction reaction was carried out for 1 hour. TLC analysis at the sampling port confirmed the completeness of the reaction. Then, 30 wt.% HOAc aqueous solution was added dropwise using an online pH controller to adjust the pH to 6, and the mixture was allowed to stand for separation. The organic layer (lower layer) was transferred to a reduction reaction processing vessel via a diaphragm pump, and then 10 wt.% NaCl aqueous solution was added, followed by stirring and washing once. The mixture was then allowed to stand for separation to obtain a dichloromethane solution of intermediate II.

[0123] The dichloromethane solution of intermediate II was transferred to an elimination reactor using a diaphragm pump. The solution was heated to 35°C with hot water and concentrated to near dryness under negative pressure, recovering the solvent dichloromethane. 500 kg of methanol and 1 kg of formic acid were pumped into the elimination reactor, followed by 50 kg of KOAc. The mixture was heated to 70°C with steam and stirred for 5 hours. A sample was taken for TLC analysis to confirm complete reaction. The mixture was then concentrated to near dryness with hot water at 70°C under negative pressure, recovering the solvent methanol. The mixture was cooled to 20°C, and 300 kg of recovered dichloromethane and 100 kg of drinking water were pumped in. The mixture was stirred, washed to remove salt, and allowed to stand for separation. The organic layer (lower layer) was transferred to an elimination reaction vessel using a diaphragm pump, and 100 kg of drinking water was added. The mixture was stirred, washed once, and allowed to stand for separation. The organic layer (lower layer) was then transferred to an elimination reactor using a diaphragm pump, heated to 40°C with hot water, and concentrated to near dryness under negative pressure, recovering the solvent dichloromethane. 80 kg of methanol was pumped in, the temperature was lowered to 4 °C, and the mixture was stirred to crystallize for 1 hour. The precipitated material was transferred to a centrifuge for centrifugation and filtration. The reaction vessel was washed with 10 kg of methanol, and the filter cake was rinsed and dried. The filter cake was then transferred to a vacuum dryer and dried at 70 °C for 6 hours to obtain 89.5 kg of a pale yellow, sandy solid (11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate).

[0124] In Example 5, the yield of product 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate was 89.5% (based on the mass of prednisolone acetate), and the purity was 99.2% as determined by HPLC.

[0125] Figure 6 This is the HPLC chromatogram of 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate in Example 5. Figure 6 The information obtained is shown in Table 5.

[0126] Table 5 Figure 6 Information data

[0127]

[0128] Comparative example:

[0129] The preparation method in Chinese patent CN 104262440 is as follows:

[0130] 100g of prednisolone acetate, 500ml of chloroform, 250ml of acetic anhydride, and 5g of p-toluenesulfonic acid were added to a three-necked reaction flask. The mixture was stirred and heated to reflux, and the reaction was maintained at this temperature for 14-16 hours. After the reaction was completed, the temperature was lowered to about 25°C, and 200ml of water was added dropwise to terminate the reaction. The mixture was concentrated under reduced pressure until it gradually dried, and 1000ml of water was added. The mixture was stirred for 30 minutes, filtered, washed with water until neutral, and dried to obtain 109g of compound II, namely 1,4,-diene-3,11,20-trionepregn-17α,21-diacetate; yield: approximately 109% by weight, HPLC purity: 99%.

[0131] Add 250 ml of methanol, 250 ml of dichloromethane, 50 g of compound II, and 30 g of anhydrous zinc chloride to a three-necked reaction flask. Dissolve completely with stirring. Cool to approximately 10-15°C. Slowly add 8 g of potassium borohydride solid in portions to the reaction solution. After the reaction is complete, adjust the pH to 6-7 with glacial acetic acid. Stir for 10 minutes after addition. If no change in pH is observed, concentrate the solvent to dryness under negative pressure at 40-50°C. Add 500 ml of water to crystallize. Disperse the solid with stirring. Filter. Wash the solid with water until neutral. Dry to obtain 48.5 g of compound III, i.e., 11β-hydroxypregn-1,4-diene-3,20-dione-17α,21-diacetate; yield 97% by weight, HPLC purity 98%.

[0132] Add 250 ml of dimethylformamide to a three-necked reaction flask, stir, and purge with nitrogen. Add 50 g of compound III and 26.5 g of anhydrous potassium acetate. Heat to 60 °C and react for 7-10 h. After the reaction is complete, cool to room temperature and pour the reaction solution into 3000 ml of ice water pre-cooled to 0 °C. Stir at 0-5 °C for 12 h, let stand for 1 h, filter, wash with ice water until neutral, filter again, and dry to obtain 35 g of compound IV, namely 11β-hydroxypregn-1,4,16(17)-triene-3,20-dione-21-acetate; yield: 70% by weight, HPLC purity: approximately 96%.

[0133] The comparative example uses a variety of solvents (chloroform, acetic anhydride, dichloromethane, methanol, and dimethylformamide) in its three-step reaction, and the amount used is large. Dimethylformamide wastewater is particularly difficult to treat. The intermediate post-processing employs a large-scale water crystallization method, resulting in significant process wastewater (approximately 100 kg wastewater / kg product). Each step requires drying of the materials before proceeding to the next reaction (energy consumption and time consumption), and the product purity and yield are only 96%. In contrast, the continuous production process and equipment used in this invention, which does not require material output, exhibit significant advantages in environmental protection, energy saving, high efficiency, and low cost.

[0134] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate, characterized in that, Includes the following steps: Prednisolone acetate, acetic anhydride, esterification catalyst, and methane chloride solvent are mixed in an esterification reactor and then subjected to an esterification reaction to obtain an esterification reaction solution; the esterification catalyst is selected from nitrogen-containing catalysts and sulfur-containing catalysts. The nitrogen-containing catalyst is selected from pyridine or triethylamine; the sulfur-containing catalyst is 2-sulfur benzoic acid or concentrated sulfuric acid; the methane chloride is chloroform or dichloromethane; The mass ratio of the nitrogen-containing catalyst to the sulfur-containing catalyst is 0.02~0.1:0.1~0.5; the mass ratio of prednisolone acetate to acetic anhydride is 1:0.5~1; the mass ratio of prednisolone acetate to the nitrogen-containing catalyst is 1:0.02~0.1; the mass ratio of prednisolone acetate to the methane chloride solvent is 1:0.5~1; the esterification reaction is carried out at a temperature of 25~35℃ for 6~8 hours. The esterification reaction solution is pumped into the first esterification reaction post-treatment vessel, and then subjected to first washing and standing for layering. The resulting first esterified organic phase is pumped into the second esterification reaction post-treatment vessel, and then subjected to impurity removal by a weak alkaline solution and standing for layering. The resulting second esterified organic phase is dried with a drying agent to obtain a solution of intermediate I. The purification with the weakly alkaline solution involves adjusting the pH of the first esterified organic phase to 6-6.5 using a NaHCO3 aqueous solution; the mass concentration of the NaHCO3 aqueous solution is 10%. The solution of intermediate I, NaBH4, reduction catalyst, and alcohol solvent are mixed in a reduction reactor and then subjected to a reduction reaction in sequence under a protective atmosphere. The HOAc aqueous solution is purified and allowed to stand for separation. The resulting reduced organic layer is pumped into a reduction reaction treatment vessel and subjected to a second washing and standing for separation to obtain a solution of intermediate II. The mass concentration of the HOAc aqueous solution is 30%. Intermediate I; Intermediate II; The reduction catalyst is calcium chloride or magnesium chloride; the reduction reaction temperature is -45~-40℃, and the holding time is 0.8~1.2h; The solution of intermediate II is pumped into an elimination reaction vessel for concentration, then mixed with an alcohol solvent, an elimination catalyst, and KOAc. The elimination reaction, concentration, extraction, and static separation are carried out sequentially to obtain an elimination reaction organic layer. The elimination catalyst is acetic acid, formic acid, or oxalic acid. The temperature of the elimination reaction is 65~85℃, and the holding time is 4~6h. The organic layer from the elimination reaction was pumped into an elimination reaction treatment vessel, washed and allowed to stand for separation. The resulting organic phase was then pumped into the elimination reaction vessel for concentration and crystallization to obtain 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate. The crystallization reagent was an alcohol solvent. The crystallization temperature was 0~10℃ and the time was 0.8~1.2h. The alcohol solvents used in the elimination reaction, reduction reaction, and crystallization are all one or more of methanol, ethanol, and tert-butanol; after crystallization, the solid obtained after crystallization is dried at a temperature of 70-80°C for 5-8 hours.

2. The preparation method according to claim 1, characterized in that, The apparatus for preparing the 11β-hydroxy-pregn-1,4,16-triene-3,20-dione-21-acetate includes an esterification reactor (1); The first esterification reaction post-treatment vessel (2) is connected to the esterification reactor via a pipeline; A second esterification reaction post-treatment vessel (3) is connected to the first esterification reaction post-treatment vessel (1) via a pipeline; A reduction reactor (4) connected to the first esterification reaction post-treatment reactor (2) via a pipeline; A reduction reaction treatment vessel (5) connected to the reduction reaction vessel via a pipeline; Elimination reactor (6) connected to reduction reaction treatment reactor via pipeline; Elimination reaction treatment vessel (7) is connected to the elimination reaction vessel via a pipeline.

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