Preparation method and application of betamethasone butyrate and propionate

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method and application of betamethasone butyrate and propionate. According to the method, the betamethasone butyrate and propionate is successfully synthesized through three-step reaction of cyclization, selective hydrolysis and acylation of betamethasone. Compared with a traditional method, the method has the advantages that the reaction conditions are obviously optimized, the solvent which is low in toxicity and easy to recover is used, selective hydrolysis is carried out by using the mesoporous silica supported sulfuric acid catalyst, and the yield and selectivity of the reaction are improved. According to the method, the use of high-toxicity solvents and the generation of waste liquid are reduced, the risk of environmental pollution is reduced, the modern environmental protection standard is met, the production cost is reduced, and the method is suitable for large-scale commercial production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method and application of betamethasone butyrate propionate. Background Art

[0002] Betamethasone Butyrate Propionate, also known as betamethasone butyrate propionate, has a chemical name of 9-fluoro-11β,17,21-trihydroxy-16β-methylpregnane-1,4-diene-3,20-dione-17-butyrate-21-propionate, and has the structural formula:

[0003]

[0004] Betamethasone butyrate propionate binds to the glucocorticoid receptors on target cells, directly inhibiting the transcriptional activation of target genes involved in inflammation and immune response and the activation of transcription factors such as NF-kB. It has an inhibitory effect on the production of inflammatory cytokines and the proliferation of T cells.

[0005] Betamethasone butyrate propionate has multiple pharmacological effects such as anti-inflammatory, anti-allergic and immunosuppressive effects:

[0006] (1) Anti-inflammatory effect: Glucocorticoids reduce and prevent tissue response to inflammation, thereby alleviating the manifestations of inflammation.

[0007] (2) Immunosuppressive effect: prevent or inhibit cell-mediated immune responses, delay allergic reactions, and reduce the expansion of primary immune responses.

[0008] (3) Anti-toxic and anti-shock effects: Glucocorticoids can counteract the stimulating response of bacterial endotoxins to the body, reduce cell damage, and play a role in protecting the body.

[0009] Betamethasone propionate butyrate is a prodrug of the glucocorticoid drug betamethasone. Compared with the original drug, two ester groups, butyrate and propionate, are added to its structure, which is more lipophilic, so it has the advantages of excellent skin permeability and long maintenance time. At present, although betamethasone dipropionate is mainly used in the domestic market, betamethasone propionate butyrate has been widely used in Japan, especially in compound drugs for the treatment of psoriasis, such as maxacalcitol betamethasone propionate butyrate ointment. Maxacalcitol has an inhibitory effect on the abnormal proliferation of epidermal keratinocytes, and betamethasone propionate butyrate has an inhibitory effect on the production of inflammatory cytokines and the proliferation of T cells. The two work synergistically, so its clinical effect is significant. The successful application of this compound drug highlights the importance of combining the advantages of different drugs to enhance the therapeutic effect. However, there is still a blank in the research on the raw materials of betamethasone propionate butyrate in China, and the development and research in this field are imminent. Expanding the research on betamethasone butyrate propionate can not only enrich existing treatment methods and bring more treatment options, but also fill the domestic research and development gap in this field, which has important clinical significance and market potential.

[0010] Although there are no public reports on the preparation of betamethasone butyrate propionate, the traditional synthesis method of betamethasone dipropionate has faced many challenges. (Zhang Yusong; Jin Weihua; Wang Weijun; Synthesis of betamethasone dipropionate [J]; Chinese Modern Applied Pharmacy; Issue 07, 2011) Betamethasone-17,21-orthopropionic acid cyclic ester is obtained by cyclization reaction of betamethasone with triethyl orthopropionate, and then selective hydrolysis at the 21st position to obtain betamethasone 17-propionate, and finally the 21st hydroxyl group is propionylated to obtain the target product. However, due to the poor solubility of betamethasone and betamethasone 17-propionate in most solvents, solvents such as tetrahydrofuran, pyridine or chloroform (all Class 2 solvents) are usually required, and these solvents have high toxicity. In addition, acetic acid is often used as a solvent in the hydrolysis reaction. Acetic acid is not only highly corrosive, but also has potential damage to the reaction equipment and is difficult to recover. At the same time, the yield of this step is low. The above problems lead to the generation of a large amount of waste liquid after the reaction, causing serious environmental pollution and not meeting current environmental protection standards. Moreover, the hydrolysis effect of acetic acid / water is poor and the yield is low, which hinders the feasibility of commercial production. To solve these problems, the present invention proposes a high-yield betamethasone butyrate propionate synthesis method. This new method significantly reduces environmental pollution, optimizes reaction conditions and costs, makes it more suitable for commercial production, and meets modern environmental protection requirements. Summary of the invention

[0011] In view of this, the present invention provides a preparation method of betamethasone butyrate propionate. The preparation method has low equipment requirements, good reaction selectivity, high yield and conforms to the concept of environmental protection, and provides effective technical support for the research and production of betamethasone butyrate propionate raw materials and preparations.

[0012] To achieve the above object, the technical solution of the present invention is:

[0013] In a first aspect, the present invention provides a method for preparing betamethasone butyrate propionate, the structural formula of which is as follows:

[0014]

[0015] The reaction route of the preparation method is as follows:

[0016]

[0017] The preparation method steps are as follows:

[0018] (1) Using the compound of formula 1 as a raw material and tert-butyl methyl ether as a solvent, adding an acid and triethyl orthobutyrate, stirring and reacting at room temperature for 2 to 3 hours, concentrating, washing the concentrate with ice water, and vacuum drying at room temperature to obtain a compound of formula 2;

[0019] (2) selectively hydrolyzing the compound of formula 2 obtained in step (1) with acid and water, filtering, purifying with ethyl acetate and n-heptane, and vacuum drying to obtain a compound of formula 3;

[0020] (3) The compound of formula 3 obtained in step (2) is dissolved in tert-butyl methyl ether, propionic anhydride is added, a base is added dropwise, reacted at room temperature for 10 hours, concentrated, and treated with ethanol, n-heptane and ethyl acetate to obtain betamethasone butyrate propionate.

[0021] According to an embodiment of the present invention, the acid used in step (1) is selected from one or more of formic acid, acetic acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid.

[0022] According to an embodiment of the present invention, the supported sulfuric acid catalyst used in step (2) is selected from mesoporous silica-supported sulfuric acid or styrene-divinylbenzene copolymer-supported sulfuric acid.

[0023] According to an embodiment of the present invention, the mesoporous silica-supported sulfuric acid catalyst is prepared by mixing mesoporous silica with sulfuric acid and reacting at 70-100° C. with magnetic stirring; wherein the mass ratio of mesoporous silica to sulfuric acid is (3-5):1.

[0024] According to an embodiment of the present invention, the preparation method of the mesoporous silica is:

[0025] Weigh surfactant APG08-10, add it into distilled water and stir to dissolve, adjust the pH value of the solution to 12 with NaOH, slowly add ethyl orthosilicate dropwise while stirring, and continue stirring at room temperature for 2 to 3 hours, seal and age at 60 to 80°C for 4 to 6 hours; filter, wash with distilled water, dry at 120°C, and calcine at 450 to 500°C for 1 hour to obtain mesoporous silica.

[0026] According to an embodiment of the present invention, the molar ratio of the surfactant APG08-10 to tetraethyl orthosilicate is 1:0.25-0.01.

[0027] According to an embodiment of the present invention, the preparation method of the styrene-divinylbenzene copolymer loaded with sulfuric acid is:

[0028] Weigh styrene-divinylbenzene copolymer resin, add it into distilled water, stir and soak for 30 minutes, wash, slowly add sulfuric acid dropwise while stirring, place on a magnetic temperature-controlled stirrer after mixing, react at 40-50° C., filter and wash; wherein the mass ratio of styrene-divinylbenzene copolymer resin to sulfuric acid is (3-5):1.

[0029] According to an embodiment of the present invention, the base used in step (3) is selected from one or more of diisopropylethylamine, N-methylmorpholine, and triethylamine.

[0030] In a second aspect, the present invention also provides application of the preparation method in drug process research, which can be used for the research and production of betamethasone butyrate propionate raw materials.

[0031] The beneficial effects of the present invention are:

[0032] The invention provides an environmentally friendly and efficient preparation method of betamethasone butyrate propionate. The method utilizes a low-toxic solvent and selects mesoporous silica-loaded sulfuric acid to catalyze the hydrolysis reaction, which significantly reduces the use of highly toxic solvents, reduces environmental pollution, and improves the yield of the reaction, achieving a final product yield of more than 65%, while improving the purity of the product, the purity of the finished product is more than 99.5%, and a single unknown impurity is less than 0.10% (according to the ICHQ3A guidelines, the maximum daily dose of the raw material drug does not exceed 2 grams / day, and the identification limit is 0.10% or 1.0 mg (the lower limit is taken) per day. The maximum daily dose of this product is much lower than 2 grams / day, so a single unknown impurity should be controlled below 0.10%). By optimizing the reaction conditions and the use of catalysts, not only the production cost is reduced, but also the economy is improved, making it suitable for commercial production. In addition, this method fills the gap in the research field of betamethasone butyrate propionate in China, and is of great significance to the research and production of related raw materials and preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the HPLC detection spectrum of betamethasone butyrate propionate related substances in Example 1.

[0034] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of betamethasone butyrate propionate in Example 1.

[0035] Figure 3It is the carbon nuclear magnetic resonance spectrum of betamethasone butyrate propionate in Example 1.

[0036] Figure 4 This is the HPLC detection spectrum of betamethasone butyrate propionate related substances in Example 2.

[0037] Figure 5 This is the HPLC detection spectrum of related substances of betamethasone butyrate propionate in Comparative Example 1. DETAILED DESCRIPTION

[0038] The present invention is further described in detail below in conjunction with specific examples and drawings. The following examples are only illustrative and not restrictive, and the protection scope of the present invention cannot be limited thereto. Unless otherwise specified, the raw materials used can be obtained from the market or homemade.

[0039] The present invention uses betamethasone as a raw material, and obtains the betamethasone butyrate propionate through three steps of cyclization, selective hydrolysis and acylation. The chemical name of the betamethasone butyrate propionate is 9-fluoro-11β,17,21-trihydroxy-16β-methylpregnane-1,4-diene-3,20-dione-17-butyrate-21-propionate, and the structural formula is:

[0040]

[0041] The invention aims to protect the preparation method of betamethasone butyrate propionate, which is used for the research and production of betamethasone butyrate propionate to ensure the product quality and medication safety of betamethasone butyrate propionate.

[0042] In the prior art, Class 2 solvents, such as tetrahydrofuran, pyridine, and chloroform, are usually used to synthesize betamethasone butyrate. However, these solvents are highly toxic and cause environmental pollution. According to the ICH Q3C residual solvent guidelines, Class 1 solvents have unacceptable toxicity or cause harm to the environment, and should not be used in the production of raw materials, excipients, and preparations; Class 2 solvents have inherent toxicity and their use in preparations should be restricted; Class 3 solvents can be considered as low-toxic solvents with a low risk of harm to human health. Therefore, when studying the synthesis method of betamethasone butyrate propionate, we selected Class 3 solvents with lower toxicity for research. Through screening and experimental verification, ethanol, acetone, ethyl acetate, tert-butyl methyl ether, and n-heptane were finally determined to be the most suitable solvents, all of which are Class 3 solvents.

[0043] Example 1

[0044] Step 1 Preparation of compound of formula 2

[0045] Reaction:

[0046]

[0047] Add 20 g of betamethasone, 200 ml of tert-butyl methyl ether and 0.19 g of p-toluenesulfonic acid to a 250 ml reaction bottle, stir, add triethyl orthobutyrate, gradually dissolve, stir at room temperature for 3 hours, and concentrate under reduced pressure to obtain a white solid. Add 150 ml of ice water and stir for 30 minutes, filter, and dry the obtained solid under vacuum at room temperature to obtain 22.50 g of compound 2, with a yield of 90.1%.

[0048] Step 2 Preparation of compound of formula 3

[0049] Reaction:

[0050]

[0051] Preparation of catalyst:

[0052] (1) Preparation of mesoporous silica: Add 10 g of APG08-10 to 300 ml of distilled water and stir until completely dissolved. Titrate with 1 M NaOH solution to adjust the pH of the solution to 12. Slowly add 2.0 g of ethyl orthosilicate under continuous stirring. Continue stirring at room temperature for 3 h. Place the mixture in a sealed environment at 60 ° C for 4 h. Separate the reaction product by filtration, wash with distilled water, and dry the sample at 120 ° C to remove moisture. Finally, calcine the dried sample at 450 ° C for 1 h to complete the formation of mesoporous silica.

[0053] (2) Sulfuric acid and mesoporous silica are mixed, and after mixing, the mixture is placed on a magnetic temperature-controlled stirrer to react at 80° C., and then placed in an oven to dry, thereby obtaining a mesoporous silica-supported sulfuric acid catalyst.

[0054] Add 20g of compound 2, 5g of mesoporous silica-supported sulfuric acid catalyst, 180ml of acetone and 30ml of water to a 250ml reaction bottle, stir at room temperature for 5 hours, filter and recover the silica-supported sulfuric acid catalyst, and wash with a small amount of water. Concentrate the filtrate under reduced pressure, add 40ml of ethyl acetate and mix evenly, heat to 65℃, stir to dissolve, add 160ml of n-heptane dropwise, cool to 25℃, crystallize for 1h, filter, and dry the solid in vacuum at 40-50℃; obtain 17.15g of compound 3, with a yield of 90.9%.

[0055] Step 3 Preparation of Betamethasone Butyrate Propionate

[0056] Reaction:

[0057]

[0058] Add 12.31 g of the compound of formula 3 and 100 ml of tert-butyl methyl ether to a 250 ml reaction bottle, stir to dissolve, add 5.19 g of propionic anhydride, add 4.12 g of triethylamine dropwise, control the temperature at 20-30°C, react at room temperature for 10 h, and concentrate to dryness to obtain an oil.

[0059] 300 ml of water and 300 ml of n-heptane were added to the oily substance, and the mixture was stirred. 300 ml of ethyl acetate was added for extraction. The layers were separated, and the organic phase was concentrated to dryness.

[0060] Add 100 ml of ethanol to the concentrate, heat to 50-60°C, filter after dissolving, heat the filtrate to 50-60°C, add 300 ml of n-heptane dropwise, cool to room temperature and stir for 3 hours, filter, wash the solid with n-heptane, and dry in vacuo at 20-30°C to obtain 12.53 g of betamethasone butyrate propionate with a purity of 99.68%, a maximum single impurity of 0.09%, and a yield of 90.8%.

[0061] The HPLC test results of related substances of betamethasone butyrate propionate are shown in Table 1, and the corresponding test spectrum is shown in Figure 1 .

[0062] Table 1

[0063] Largest single impurity Total impurities Betamethasone butyrate propionate Peak time (min) 6.626 / 8.009 Peak area ratio (%) 0.09 0.32 99.68

[0064] Betamethasone butyrate propionate H NMR spectrum Figure 2 , NMR carbon spectrum Figure 3 .

[0065] 1 H NMR (400MHz, CDCl3): δ7.2359-7.2106 (d, 1H), 6.3722-6.3424 (t, 1H), 6.1379 (s, 1H), 4.8596-4.8187 ( d, 1H), 4.4439-4.4237 (d, 1H), 4.3348-4.22939 (d, 1H), 2.6850-2.6043 (m, 1H), 2.4839-2.4252 (m, 6H), 2.3480-2.3064(m, 2H), 2.1571-2.1161(m, 2H), 2.0148-1.8858(m, 4H), 1.6819-1.6262(m, 3H), 1.5603 (s, 3H), 1.3589-1.3406 (d, 3H), 1.2624-1.2590 (d, 1H), 1.2336-1.1503 (m, 3H), 0.9954-0.9371 (m, 3H).

[0066] 13C NMR (101MHz, CDCl3): δ198.56, 186.47, δ174.29, 174.14, 165.86, 165.85, 151.92, 129.89, 125.15, 100.97, 99.22, 94, 47, 71.99, 71.62, 67 .98, 48.21, 47.99, 47.70, 43.63, 36.93, 36.77, 34.77, 33.85, 33.65, 30.97, 27.69, 27.11, 23.05, 22.99, 19.44, 18.14, 16.29, 13.76, 8.99.

[0067] ESI-MS: m / z: 519.46 [M+H] + ,m / z:563.49[M+HCOO] - .

[0068] Example 2

[0069] Step 1 Preparation of compound of formula 2

[0070] Reaction:

[0071]

[0072] Add 20 g of betamethasone, 200 ml of tert-butyl methyl ether and 0.17 g of benzenesulfonic acid to a 250 ml reaction bottle, stir, add triethyl orthobutyrate, stir to dissolve, stir at room temperature for 3 hours, and concentrate under reduced pressure to obtain a white solid. Add 150 ml of ice water and stir for 30 minutes, filter, and dry the obtained solid under vacuum at room temperature to obtain 22.81 g of compound 2, with a yield of 91.3%.

[0073] Step 2 Preparation of compound of formula 3

[0074] Reaction:

[0075]

[0076] Preparation of catalyst:

[0077] (1) Pretreatment of resin: 10 g of styrene-divinylbenzene copolymer resin was placed in 100 ml of distilled water, stirred and soaked for 30 minutes, and the resin was repeatedly washed with distilled water until the washing liquid became clear.

[0078] (2) Sulfuric acid and resin are mixed, and after mixing, they are placed on a magnetic temperature-controlled stirrer, reacted at 50° C., filtered, and washed to obtain a styrene-divinylbenzene copolymer-loaded sulfuric acid catalyst.

[0079] Add 20g of compound 2, 5g of styrene-divinylbenzene copolymer-supported sulfuric acid catalyst, 180ml of acetone and 30ml of water to a 250ml reaction bottle, stir at room temperature for 5 hours, filter with suction, and wash with a small amount of water. Concentrate the filtrate, add 40ml of ethyl acetate and mix evenly, heat to 65°C and stir to dissolve, add 160ml of n-heptane dropwise, cool to 25°C, crystallize for 1h, filter with suction, and dry the solid at 45°C in vacuum to obtain 16.97g of compound 3, with a yield of 89.6%.

[0080] Step 3 Preparation of Betamethasone Butyrate Propionate

[0081] Reaction:

[0082]

[0083] Add 12.52 g of the compound of formula 3 and 100 ml of tert-butyl methyl ether to a 250 ml reaction bottle, stir to dissolve, add 5.21 g of propionic anhydride, add 4.5 g of diisopropylethylamine dropwise, control the temperature at 20-30°C, react at room temperature for 10 h, and concentrate to dryness to obtain an oil.

[0084] 300 ml of water and 300 ml of n-heptane were added to the oily substance, and the mixture was stirred. 300 ml of ethyl acetate was added for extraction. The layers were separated, and the organic phase was concentrated to dryness.

[0085] Add 100 ml of ethanol to the concentrate, heat to 50-60°C, filter after dissolving, heat the filtrate to 50-60°C, add 300 ml of n-heptane dropwise, cool to room temperature and stir for 3 hours, filter, wash the solid with n-heptane, and dry in vacuo at 20-30°C to obtain 12.38 g of betamethasone butyrate propionate with a purity of 99.81%, a maximum single impurity of 0.06%, and a yield of 88.2%.

[0086] The HPLC test results of related substances of betamethasone butyrate propionate are shown in Table 2, and the corresponding test spectrum is shown in Figure 4 .

[0087] Table 2

[0088] Largest single impurity Total impurities Betamethasone butyrate propionate Peak time (min) 32.635 / 8.001 Peak area ratio (%) 0.06 0.19 99.81

[0089] Comparative Example 1

[0090] Step 1 Preparation of compound of formula 2

[0091] Reaction:

[0092]

[0093] Add 20 g of betamethasone, 200 ml of 2-methyltetrahydrofuran and 0.17 g of p-toluenesulfonic acid to a 250 ml reaction bottle, stir, add triethyl orthobutyrate, stir to dissolve, stir at room temperature for 3 hours, and concentrate under reduced pressure at 30°C water bath to obtain a white solid. Add 150 ml of ice water and stir for 30 minutes, filter, and dry the obtained solid under vacuum at room temperature to obtain 20.31 g of compound 2, with a yield of 81.3%.

[0094] Step 2 Preparation of compound of formula 3

[0095] Reaction:

[0096]

[0097] Add 20g of compound 2, 190ml of acetic acid and 30ml of water to a 250ml reaction bottle, stir at room temperature for 25 hours, filter with suction, and wash with a small amount of water. Mix the obtained solid with 40ml of ethyl acetate, heat to 65℃, stir to dissolve, add 160ml of n-hexane dropwise, cool to 25℃, crystallize for 1h, filter with suction, and dry the solid in vacuum at 45℃ to obtain 10.47g of compound 3, with a yield of 55.5%.

[0098] Step 3 Preparation of Betamethasone Butyrate Propionate

[0099] Reaction:

[0100]

[0101] Add 10.21 g of the compound of formula 3 and 100 ml of 2-methyltetrahydrofuran into a 250 ml reaction bottle, stir to dissolve, add 4.29 g of propionic anhydride, add 4.5 g of triethylamine dropwise, control the temperature at 20-30°C, react at room temperature for 45 hours, and concentrate to dryness to obtain an oil.

[0102] Add 300 ml of water and 300 ml of n-hexane to the oily substance, stir, add 300 ml of dichloromethane for extraction, separate the layers, concentrate the organic phase to dryness, add 200 ml of water, stir at room temperature for 3 hours, filter, wash the solid with water, and dry in vacuo at 30°C to obtain 9.22 g of betamethasone butyrate propionate, with a purity of 99.48%, a maximum single impurity of 0.16%, and a yield of 80.5%. The HPLC test results of related substances of betamethasone butyrate propionate are shown in Table 3, and the corresponding test spectrum is shown in Figure 5 .

[0103] Table 3

[0104] Largest single impurity Total impurities Betamethasone butyrate propionate Peak time (min) 32.625 / 8.004 Peak area ratio (%) 0.16 0.52 99.48

Claims

1. A method for preparing a betamethasone butyrate propionate raw material drug, the structural formula of which is as follows: It is characterized in that The reaction route of the preparation method is as follows:

2. The preparation method according to claim 1, characterized in that: The preparation method steps are as follows: The preparation method steps are as follows: (1) Using the compound of formula 1 as a raw material and tert-butyl methyl ether as a solvent, adding an acid and triethyl orthobutyrate, stirring and reacting at room temperature for 2 to 3 hours, concentrating, washing the concentrate with ice water, and vacuum drying at room temperature to obtain a compound of formula 2; (2) hydrolyzing the compound of formula 2 obtained in step (1) under the catalysis of supported sulfuric acid, filtering, purifying with ethyl acetate and n-heptane, and vacuum drying to obtain a compound of formula 3; (3) The compound of formula 3 obtained in step (2) is dissolved in tert-butyl methyl ether, propionic anhydride is added, a base is added dropwise, and the mixture is reacted at room temperature for 8 to 10 hours, concentrated, and treated with ethanol, n-heptane and ethyl acetate to obtain betamethasone butyrate propionate.

3. The preparation method according to claim 2, characterized in that: The acid used in step (1) is selected from one or more of formic acid, acetic acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid.

4. The preparation method according to claim 2, characterized in that: The supported sulfuric acid catalyst used in step (2) is selected from mesoporous silica supported sulfuric acid or styrene-divinylbenzene copolymer supported sulfuric acid.

5. The preparation method according to claim 4, characterized in that: The mesoporous silica-supported sulfuric acid catalyst is prepared by mixing mesoporous silica with sulfuric acid and reacting them at 70-100° C. with magnetic stirring; wherein the mass ratio of the mesoporous silica to the sulfuric acid is (3-5):

1.

6. The preparation method according to claim 4, characterized in that: The preparation method of the mesoporous silica is: Weigh surfactant APG08-10, add it into distilled water and stir to dissolve, adjust the pH value of the solution to 12 with NaOH, slowly add ethyl orthosilicate dropwise while stirring, and continue stirring at room temperature for 2 to 3 hours, seal and age at 60 to 80°C for 4 to 6 hours; filter, wash with distilled water, dry at 120°C, and calcine at 450 to 500°C for 1 hour to obtain mesoporous silica.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the surfactant APG08-10 to tetraethyl orthosilicate is 1:0.25-0.

01.

8. The preparation method according to claim 4, characterized in that: The preparation method of the styrene-divinylbenzene copolymer loaded with sulfuric acid is: Weigh styrene-divinylbenzene copolymer resin, add it into distilled water, stir and soak for 30 minutes, wash, slowly add sulfuric acid dropwise while stirring, place on a magnetic temperature-controlled stirrer after mixing, react at 40-50° C., filter and wash; wherein the mass ratio of styrene-divinylbenzene copolymer resin to sulfuric acid is (3-5):

1.

9. The preparation method according to claim 2, characterized in that: The base used in step (3) is selected from one or more of diisopropylethylamine, N-methylmorpholine and triethylamine.

10. Application of the preparation method according to any one of claims 1 to 9 in pharmaceutical process research, which can be used for the research and production of betamethasone butyrate propionate raw materials and preparations.

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