Preparation process of hydrocortisone acetate
By using compound 1 as the starting material and combining carbonyl protection, reductive hydrolysis and displacement reactions, the problems of long reaction routes and low yields in the synthesis of hydrocortisone acetate were solved, achieving efficient and environmentally friendly industrial production and improving product quality and yield.
Patent Information
- Application Number
- CN202511720344.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-21
- Publication Date
- 2026-02-10
AI Technical Summary
Existing methods for synthesizing hydrocortisone acetate suffer from problems such as long reaction routes, low yields, numerous byproducts, environmental unfriendliness, high costs, and difficulty in large-scale production.
Using compound 1 as the starting material, the operation process is simplified through carbonyl protection, reductive hydrolysis and displacement reactions. Ethylene glycol and alcohol reagents are used to replace aminourea, and the chloride is directly converted to the ester, reducing side reactions and improving conversion rate and yield.
It shortens the reaction route, increases product yield and purity, reduces production costs, is suitable for large-scale industrial production, and reduces the generation of high-nitrogen wastewater.
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Figure CN121494909A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical and chemical technology, and in particular to a preparation process for hydrocortisone acetate. Background Technology
[0002] Hydrocortisone acetate ( Hydrocortisone acetate, also known as hydrocortisone-21-acetate, hydrocortisone acetate, or hydrocortisone acetonide, has a melting point of 222–225°C. It is a white to off-white powder, slightly soluble in methanol, ethanol, or chloroform, and insoluble in water. It belongs to the class of glucocorticoids and is a topical corticosteroid with anti-inflammatory, anti-allergic, antitoxin, and anti-shock effects. It is mainly used to treat rheumatoid arthritis, rheumatic fever, gout, and bronchial asthma. Currently, the main synthetic methods for hydrocortisone acetate are semi-synthetic and total synthesis. Semi-synthetic methods primarily utilize Rhizopus nigricans and Rhizopus thuringiensis methods. While research abroad has also used Curvularia crescentis, its use in industrial production in China is limited due to risks such as numerous byproducts and low conversion rates. Total synthesis methods typically involve long process routes, low yields, the use of numerous toxic and harmful reagents, and environmental unfriendliness. Among the domestic patents are redox preparation methods using cortisone acetate as raw material and one-step esterification methods using hydrocortisone as raw material. Chinese patent CN102827231 uses cortisone acetate as raw material, and through aminourea ketal, reduction reaction, deprotection, and esterification reaction, hydrocortisone acetate is obtained. The reaction route is as follows:
[0003] This method suffers from drawbacks in the deprotection process, including poor reaction selectivity, difficulty in product crystallization, the need for multiple extractions, and low yield of hydrocortisone. These limitations restrict its industrial-scale production, resulting in high costs and long production cycles. Chinese patent CN105294800 improves upon patent CN102827231 by changing the order of substitution and deprotection to obtain hydrocortisone acetate. The reaction route is as follows:
[0004] This method addresses some of the product agglomeration issues by changing the order of displacement and deprotection steps. However, the post-processing still relies on methods such as material settling and decantation, limiting scalability. Furthermore, the resulting solid is a sticky, lumpy substance, indicating low content and difficulty in agglomeration. Additionally, the continued use of amino acids as the top-protecting agent results in high-nitrogen wastewater after deprotection, further complicating wastewater treatment.
[0005] In addition, some journal articles and Chinese patents use hydrocortisone as a raw material to esterify it in one step to obtain hydrocortisone acetate. Although this method is simple to operate and has few side reactions, it still involves the source of hydrocortisone. A large number of preliminary synthesis steps are still required to meet the requirements and supply the raw materials, which indirectly increases the material cost and production cost. It also still has problems such as a long reaction route.
[0006] Therefore, this invention proposes a preparation process for hydrocortisone acetate. Summary of the Invention
[0007] In view of the above problems, this invention proposes an environmentally friendly and effective solution that overcomes the difficulties in operation and long reaction routes of the aforementioned production process, avoids the use of aminourea and other substances that easily cause high-nitrogen wastewater, and is suitable for large-scale production. It shortens the reaction route, reduces production costs, and significantly improves product quality and yield.
[0008] This invention is achieved through the following technical solution: a preparation process for hydrocortisone acetate, the preparation process comprising the following steps: S1: Carbonyl protection reaction: Ethylene glycol, triethyl orthoformate, and compound 1 were added to the reaction flask in sequence, followed by p-toluenesulfonic acid. The reaction was carried out under controlled temperature. After the reaction was completed, water was added to crystallize the compound, which was then filtered and dried to obtain compound 2. S2: Reduction hydrolysis reaction: Add tetrahydrofuran and water to compound 2, stir and add sodium borohydride in batches to carry out reduction reaction. After the reaction is complete, add quenching agent to quench the reaction, add inorganic acid, stir at room temperature for more than 2 hours, remove protection, concentrate under reduced pressure to remove solvent, add water to precipitate and cool, filter to obtain compound 3. S3: Displacement reaction: Compound 3 is added to the reaction solvent, potassium acetate is added, the temperature is raised and the reaction is completed. After the reaction is completed, the temperature is lowered, water is added to crystallize, and the crude product of hydrocortisone acetate is obtained by filtration. The crude product is dissolved in dichloromethane and water to remove salt, washed with water to separate the layers, concentrated to dryness, and discharged by crystallization in alcohol solvent to obtain the refined product of hydrocortisone acetate.
[0009] Preferably, the structural formula of compound 1 is as follows:
[0010] Preferably, in step (1), the weight ratio of p-toluenesulfonic acid to compound 1 is 1:(25-100); the weight ratio of compound 1: ethylene glycol: triethyl orthoformate is 1:(2.2-3.6):(1.4-1.8).
[0011] Preferably, in step (2), the weight ratio of compound 2: tetrahydrofuran: water is 1:(5.3-7.4):(2-3.3); the weight ratio of sodium borohydride to compound 2 is 1:(2-3.3).
[0012] Preferably, in step (3), the weight ratio of compound 3 to reaction solvent is 1:(2-8.8); the weight ratio of compound 3 to potassium acetate is 1:(0.8-1.82).
[0013] Preferably, in step 1, the temperature is controlled at 20-30℃ and the reaction time is 3-5 hours.
[0014] Preferably, in step 3, the temperature is raised to 55-75°C and the reaction is carried out for 3-7 hours.
[0015] Preferably, in step (2), the amount of inorganic acid used is 0.2 to 2 W of compound 2, and the inorganic acid is one of acetic acid, hydrochloric acid or sulfuric acid.
[0016] Preferably, in step (3), the reaction solvent is one of acetone, DMF or butyl acetate.
[0017] Preferably, in step (3), the amount of alcohol solvent used is 1 to 5% of compound 3; the alcohol solvent is one or two of methanol, ethanol or isopropanol.
[0018] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention uses compound 1 as the starting material. Compared with other technologies that use cortisone acetate as the starting material, compound 1 is an upstream intermediate for the synthesis of cortisone acetate and has a stable source of materials in our company, which shortens the reaction route by one or even several steps. (2) In this invention, ethylene glycol is used as a protective agent. Compared with aminourea in other technologies, alcohol reagents have greatly reduced material costs and safety. Moreover, the reaction has no side reactions, high conversion rate, and yield close to theoretical yield. (3) In the deprotection step, the reduction and hydrolysis deprotection are combined into one, which simplifies the operation, saves the process of secondary material processing, and is more suitable for industrial-scale production. (4) In the substitution step, the chloride is directly converted to the ester to obtain hydrocortisone acetate, skipping the process of first obtaining hydrocortisone and then performing the esterification operation, thus shortening the reaction route. (5) In the displacement step, acetone, DMF or butyl acetate are used as reaction solvents. The product has low solubility, but the impurities contained therein have relatively high solubility. After the reaction is completed, the product is cooled, water is added to crystallize and filter, which can remove most of the impurities. Then, the product is dissolved and desalted. The alcohol purification process is simple and convenient, and the product yield is high and the purity is high. Attached Figure Description
[0019] Figure 1 This is a synthetic route diagram of the present invention; Figure 2 The hydrogen spectrum of compound 1; Figure 3 The high-performance liquid chromatogram of compound 2 in Example 1; Figure 4 The high-performance liquid chromatogram of compound 3 in Example 1; Figure 5 The high-performance liquid chromatogram of hydrocortisone acetate obtained in Example 1; Figure 6 This is the high-performance liquid chromatogram of compound 2 in Example 2; Figure 7 The high-performance liquid chromatogram of compound 3 in Example 2; Figure 8 The high-performance liquid chromatogram of hydrocortisone acetate obtained in Example 2; Figure 9 The high-performance liquid chromatogram of compound 2 in Example 3; Figure 10 This is the high-performance liquid chromatogram of compound 3 in Example 3; Figure 11 The high-performance liquid chromatogram of hydrocortisone acetate obtained in Example 3; Figure 12 The high-performance liquid chromatogram of compound 2 in Example 4; Figure 13 The high-performance liquid chromatogram of compound 3 in Example 4; Figure 14 The high-performance liquid chromatogram of hydrocortisone acetate obtained in Example 4; Figure 15 The high-performance liquid chromatogram of the product obtained during the amination reduction reaction in Comparative Example 1 is shown. Figure 16 The high-performance liquid chromatogram of the reduced product obtained in Comparative Example 1; Figure 17 The high-performance liquid chromatogram of the esterified product obtained in Comparative Example 1; Figure 18 The image shows the high-performance liquid chromatogram of hydrocortisone acetate obtained in Comparative Example 1. Detailed Implementation
[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly described below. Obviously, the drawings described below are merely some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without creative effort.
[0021] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The embodiments cannot be described in detail here, but the embodiments of the present invention are not limited to the following embodiments.
[0022] The structural formula of compound 1 is as follows:
[0023] The proton spectrum of compound 1, such as Figure 2 As shown, the hydrogen spectrum data are: λ = 5.92 (s, 1H), λ = 5.64 (s, 1H), λ = 4.75 (d, 1H), λ = 4.48 (d, 1H), λ = 3.89 (d, 3H), λ = 2.88 (m ,1H), λ=2.60 (m,3H), λ=2.40 (m,3H), λ=2.15 (m,3H), λ=1.80 (m,3H), λ=1.33 (m,3H), λ=1.20 (m,1H).
[0024] Example 1: like Figure 1 As shown, a method for preparing hydrocortisone acetate includes the following steps: Carbonyl protection: 50g of compound 1 was added to a reaction flask, along with 100mL of ethylene glycol and 100mL of triethyl orthoformate. 0.5g of p-toluenesulfonic acid was added with stirring, and the reaction was carried out at room temperature (around 20℃) for 5 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, 500mL of water was slowly added dropwise for precipitation. After the addition was complete, the mixture was stirred at 0-5℃ for 2 hours to crystallize. The crystals were filtered, washed with water, and dried under forced air to obtain 61.3g of compound 2. The chromatogram is attached. Figure 3 ; Reductive hydrolysis: 50g of compound 2 was added to a reaction flask, along with 300mL of tetrahydrofuran and 100mL of water. The mixture was purged with nitrogen and stirred thoroughly. Then, 20g of sodium borohydride was added in portions, 5 minutes apart. After the addition was complete, the mixture was heated to reflux and reacted for 6.5 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, the temperature was lowered to 25°C, a quencher was added, followed by 10mL of concentrated hydrochloric acid. The mixture was stirred at room temperature for 2 hours. Sodium bicarbonate solution was added to neutralize the solution. The tetrahydrofuran was removed by concentration under reduced pressure. 100mL of water was added for precipitation. The mixture was filtered, dried, and 37.5g of compound 3 was obtained. The chromatogram is attached. Figure 4 ; Displacement reaction: 30g of compound 3, 60mL of DMF, 18g of potassium acetate, and 1.0g of alkali metal catalyst were added to the reaction flask. The temperature was raised to 60-70℃ and maintained for 3 hours. The reaction was found to be within acceptable limits by TLC. After the reaction was completed, the reaction system was cooled to -5℃, and 150mL of water was added to induce crystallization for 1 hour. The crude product was then filtered to obtain the crude product. The crude product was added to 300mL of dichloromethane and 150mL of water and stirred until dissolved. The layers were separated, the organic phase was washed with water, and the mixture was concentrated to dryness under reduced pressure. 90mL of methanol was added and stirred at -5℃ to induce crystallization for 2 hours. The mixture was then filtered and dried to obtain 28g of hydrocortisone acetate. The HPLC purity was 99.687%, the total yield was 85.8%, and the melting point was 223℃. The chromatogram is attached. Figure 5.
[0025] Example 2: A method for preparing hydrocortisone acetate, the method comprising the following steps: Carbonyl protection: 50 g of compound 1 was added to a reaction flask, along with 150 mL of ethylene glycol and 80 mL of triethyl orthoformate. 1.0 g of p-toluenesulfonic acid was added with stirring, and the reaction was carried out at 30 °C for 4 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, 500 mL of water was slowly added dropwise for precipitation. Crystallization was carried out at 0-10 °C with stirring for 2 hours. The crystals were filtered, washed with water, and dried under forced air to obtain 60.6 g of compound 2. The chromatogram is attached. Figure 6 ; Reductive hydrolysis: 50g of compound 2 was added to a reaction flask, followed by 400mL of tetrahydrofuran and 120mL of water. The mixture was purged with nitrogen and stirred thoroughly. Then, 15g of sodium borohydride was added in portions, 10 minutes apart. After the addition was complete, the mixture was heated to reflux and reacted for 8 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, the temperature was lowered to 25°C, a quencher was added, followed by 5mL of 50% sulfuric acid. The mixture was stirred at room temperature for 6 hours. Sodium carbonate aqueous solution was added to neutralize the solution. The tetrahydrofuran was removed by concentration under reduced pressure. 200mL of water was added for precipitation. The mixture was filtered, dried, and 35.9g of compound 3 was obtained. The chromatogram is attached. Figure 7 ; Displacement reaction: 30g of compound 3 was added to a reaction flask, along with 150mL of acetone, 24g of potassium acetate, and 1.5g of alkali metal catalyst. The mixture was heated to 55-65℃ and reacted for 6 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, the reaction system was cooled to -5℃, and 200mL of water was added to induce crystallization for 1 hour. The mixture was then filtered to obtain the crude product. The crude product was added to 300mL of dichloromethane and 150mL of water, stirred until dissolved, and separated into layers. The organic phase was washed with water, concentrated under reduced pressure to dryness, and 90mL of methanol was added. The mixture was stirred at -5℃ to induce crystallization for 2 hours. The crystals were then filtered and dried to obtain 29.2g of hydrocortisone acetate. The HPLC purity was 99.67%, the total yield was 84.7%, and the melting point was 224℃. The chromatogram is attached. Figure 8 .
[0026] Example 3: A method for preparing hydrocortisone acetate, the method comprising the following steps: Carbonyl protection: 25 g of compound 1 was added to a reaction flask, along with 80 mL of ethylene glycol and 40 mL of triethyl orthoformate. 1.0 g of p-toluenesulfonic acid was added with stirring, and the mixture was reacted at 30 °C for 3 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, 250 mL of water was slowly added dropwise for precipitation. Crystallization was carried out at 0-10 °C with stirring for 2 hours. The crystals were filtered, washed with water, and dried under forced air to obtain 29.6 g of compound 2. The chromatogram is attached. Figure 9 ; Reductive hydrolysis: 25g of compound 2 was added to a reaction flask, followed by 200mL of tetrahydrofuran and 80mL of water. The mixture was purged with nitrogen and stirred thoroughly. Then, 8g of sodium borohydride was added in portions, 10 minutes apart. After the addition was complete, the mixture was heated to reflux and reacted for 8 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, the temperature was lowered to 25°C, a quencher was added, followed by 10mL of glacial acetic acid. The mixture was stirred at room temperature for 10 hours. Sodium carbonate aqueous solution was added to adjust the pH to neutral. The mixture was concentrated under reduced pressure to remove tetrahydrofuran. 100mL of water was added for precipitation. The solution was filtered, dried, and 17.6g of compound 3 was obtained. The chromatogram is attached. Figure 10 ; Displacement reaction: 15g of compound 3 was added to a reaction flask, along with 150mL of butyl acetate, 18g of potassium acetate, and 1.0g of alkali metal catalyst. The mixture was heated to 65-75℃ and reacted for 7 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, the reaction system was cooled to -5℃, and 100mL of water was added to induce crystallization for 1 hour. The mixture was then filtered to obtain the crude product. The crude product was added to 200mL of dichloromethane and 100mL of water, stirred until dissolved, and separated into layers. The organic phase was washed with water, concentrated under reduced pressure to dryness, and 50mL of ethanol was added. The mixture was stirred at 0℃ to induce crystallization for 2 hours. The crystals were then filtered and dried to obtain 14.8g of hydrocortisone acetate. The HPLC purity was 99.871%, the overall yield was 82.2%, and the melting point was 224℃. The chromatogram is attached. Figure 11 .
[0027] Example 4: A method for preparing hydrocortisone acetate, the method comprising the following steps: Carbonyl protection: 25g of compound 1 was added to a reaction flask, along with 70mL of ethylene glycol and 38mL of triethyl orthoformate. 1.0g of p-toluenesulfonic acid was added with stirring, and the reaction was carried out at 30℃ for 4 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, 300mL of water was slowly added dropwise for precipitation. Crystallization was carried out at 5-10℃ with stirring for 2 hours. The crystals were filtered, washed with water, and dried under forced air to obtain 30.1g of compound 2. The chromatogram is attached. Figure 12 ; Reductive hydrolysis: 30g of compound 2 was added to a reaction flask, followed by 250mL of tetrahydrofuran and 100mL of water. The mixture was purged with nitrogen and stirred thoroughly. Then, 15g of sodium borohydride was added in portions, 10 minutes apart. After the addition was complete, the mixture was heated to reflux and reacted for 8 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, the temperature was lowered to 25℃, a quencher was added, along with 8mL of glacial acetic acid and 3mL of hydrochloric acid. The mixture was stirred at room temperature for 8 hours. Sodium carbonate aqueous solution was added to adjust the pH to neutral. The mixture was concentrated under reduced pressure to remove tetrahydrofuran. 150mL of water was added for precipitation. The solution was filtered, dried, and 20.8g of compound 3 was obtained. The chromatogram is attached. Figure 13 ; Displacement reaction: 20g of compound 3 was added to a reaction flask, along with 100mL of acetone, 50mL of LDM, and 11g of potassium acetate. The mixture was heated to 55-65℃ and maintained at this temperature for 5 hours. TLC analysis showed the reaction was satisfactory. After the reaction was complete, the reaction system was cooled to 0℃, and 300mL of water was added to induce crystallization for 1 hour. The mixture was then filtered to obtain the crude product. The crude product was added to 200mL of dichloromethane and 100mL of water, and stirred until dissolved. The mixture was separated into layers, and the organic phase was washed with water. The mixture was concentrated to dryness under reduced pressure. 60mL of isopropanol and 20mL of methanol were added, and the mixture was stirred at -10 to -5℃ to induce crystallization for 1.5 hours. The mixture was then filtered, dried, and 20.8g of hydrocortisone acetate was obtained. The HPLC purity was 99.941%, the total yield was 86.7%, and the melting point was 224℃. The chromatogram is attached. Figure 14 .
[0028] Comparative Example 1: A method for preparing hydrocortisone acetate, the method comprising the following steps: Amination reduction reaction: Add 20g of cortisone acetate, 400mL of methanol, 18g of aminourea hydrochloride, and 7g of sodium hydroxide to the reaction flask. Stir the reaction at 50-55℃ overnight. See the attached spectrum for detection. Figure 15 Sodium hydroxide was added to the reaction solution to adjust the pH to weakly alkaline, and the temperature was lowered to 20-30℃. 4.5g of sodium borohydride was added in portions to carry out the reduction reaction. After the addition was complete, the reaction was maintained at this temperature for 6-7 hours. Acetic acid was added to quench the reaction, and the methanol was removed by concentration under reduced pressure. Water was added to induce crystallization, and the mixture was filtered to obtain 22.4g of the reduced product. The spectrum is attached. Figure 16 ; Esterification reaction: Add 20g of reducing agent, 80mL of acetone, 10g of potassium acetate, 40g of acetic anhydride, and 7g of acetic acid to the reaction flask. Reflux at 50-60℃ for 6 hours. After the reaction is complete, cool the reaction system to -5℃, add 280mL of water to crystallize for 1 hour, filter, dry, and obtain 19.2g of esterified product. See attached spectrum. Figure 17 ; Deprotection reaction: 19g of reducing agent was added to the reaction flask, followed by 200mL of dilute hydrochloric acid and 40mL of chloroform. The mixture was stirred to dissolve the precipitate, and sodium nitrite aqueous solution was slowly added dropwise. Agglomeration occurred during this process. The mixture was stirred overnight at room temperature. The precipitate was separated from the liquid, and 100mL of methanol was added to the precipitate to induce crystallization. The crystals were filtered to obtain 9.6g of crude hydrocortisone acetate. The crude product was dissolved in dichloromethane and methanol, decolorized, purified, and concentrated under reduced pressure. The product was discharged from the methanol to obtain 8.0g of purified hydrocortisone acetate. HPLC purity: 97.178%, total yield: 45.2%. (See attached chromatogram). Figure 18 .
[0029] The comparative example is a route verification based on Chinese patent CN105294800. The final product purity was only 97.178%, and other intermediates contained large impurities. The hydrolysis yield was lower than expected, post-processing was difficult, and the overall yield and quality were far inferior to the product obtained by this invention.
[0030] The preparation method of hydrocortisone acetate provided by the present invention has been described in detail above. Specific examples have been used to illustrate the principle and implementation of the present invention. The description of the above embodiments is only for the purpose of helping to understand the method and core idea of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation and application scope based on the idea of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.
Claims
1. A preparation process for hydrocortisone acetate, characterized in that, The preparation process includes the following steps: S1: Carbonyl protection reaction: Ethylene glycol, triethyl orthoformate, and compound 1 were added to the reaction flask in sequence, followed by p-toluenesulfonic acid. The reaction was carried out under controlled temperature. After the reaction was completed, water was added to crystallize the compound, which was then filtered and dried to obtain compound 2. S2: Reduction hydrolysis reaction: Add tetrahydrofuran and water to compound 2, stir and add sodium borohydride in batches to carry out reduction reaction. After the reaction is complete, add quenching agent to quench the reaction, add inorganic acid, stir at room temperature for more than 2 hours, remove protection, concentrate under reduced pressure to remove solvent, add water to precipitate and cool, filter to obtain compound 3. S3: Displacement reaction: Compound 3 is added to the reaction solvent, potassium acetate is added, the temperature is raised and the reaction is completed. After the reaction is completed, the temperature is lowered, water is added to crystallize, and the crude product of hydrocortisone acetate is obtained by filtration. The crude product is dissolved in dichloromethane and water to remove salt, washed with water to separate the layers, concentrated to dryness, and discharged by crystallization in alcohol solvent to obtain the refined product of hydrocortisone acetate.
2. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, The structural formula of compound 1 is as follows: 。 3. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step (1), the weight ratio of p-toluenesulfonic acid to compound 1 is 1:(25-100); the weight ratio of compound 1: ethylene glycol: triethyl orthoformate is 1:(2.2-3.6):(1.4-1.8).
4. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step (2), the weight ratio of compound 2: tetrahydrofuran: water is 1:(5.3-7.4):(2-3.3); the weight ratio of sodium borohydride to compound 2 is 1:(2-3.3).
5. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step (3), the weight ratio of compound 3 to reaction solvent is 1:(2-8.8); the weight ratio of compound 3 to potassium acetate is 1:(0.8-1.82).
6. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step 1, the temperature is controlled at 20-30℃, and the reaction is carried out for 3-5 hours.
7. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step 3, the temperature is increased to 55-75℃, and the reaction is carried out for 3-7 hours.
8. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step (2), the amount of inorganic acid used is 0.2 to 2 W of compound 2, and the inorganic acid is one of acetic acid, hydrochloric acid or sulfuric acid.
9. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step (3), the reaction solvent is one of acetone, DMF or butyl acetate.
10. The preparation process of hydrocortisone acetate according to claim 1, characterized in that, In step (3), the amount of alcohol solvent used is 1 to 5% of compound 3; the alcohol solvent is one or two of methanol, ethanol or isopropanol.