A kind of preparation process of betamethasone

Abstract

The invention provides a preparation process of betamethasone, belonging to the technical field of medical materials; the preparation process comprises the following steps: preparing a boron trifluoride ether complex; preparing a crude betamethasone product; preparing polysorbate 80; and recrystallizing to obtain betamethasone. The modified boron trifluoride ether of the invention is a boron trifluoride ether complex, which can improve the reaction activity and selectivity of boron trifluoride, reduce the corrosiveness of boron trifluoride ether to equipment, and improve the solubility and safety of boron trifluoride ether in solvents, and is conducive to improving the yield of the ring-opening fluorination reaction of betamethasone epoxide, thereby improving the generation of the target product.

Description

Technical Field

[0001] The invention relates to the technical field of medical materials, and in particular to a preparation process of betamethasone. Background Art

[0002] Betamethasone is a highly effective halogenated corticosteroid drug that can act on the body's sugar metabolism process, thereby alleviating the pathological changes caused by the body's tissues responding to damaging stimuli. It has high efficacy and few side effects. It can treat serious diseases such as lupus erythematosus, rheumatoid arthritis, and asthma, and is widely used in international clinical practice.

[0003] At present, the most widely used betamethasone preparation process includes the following steps: fluorination of betamethasone epoxide, water precipitation, alkali adjustment, centrifugation to obtain a crude product, and the crude product is then subjected to recrystallization and water washing processes to obtain high-purity betamethasone fine products. Although this process can obtain high-purity betamethasone, there are still problems such as low product yield and large amount of wastewater generated in the process.

[0004] In summary, a preparation process for betamethasone with high product yield and capable of reducing wastewater discharge is developed. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention aims to provide a preparation process of betamethasone.

[0006] A preparation process of betamethasone, characterized in that it comprises the following steps:

[0007] S1: Preparation of Boron Trifluoride Ether Complex

[0008] A quantitative amount of fuming sulfuric acid is added into a reaction kettle, and boric anhydride and fluorite powder are added and stirred to generate boron fluoride gas, and the boron fluoride gas is gas-phase complexed with ether gas evaporated from an ether vaporizer, and then distilled in a distiller to obtain a boron trifluoride ether complex;

[0009] S2: Preparation of crude betamethasone

[0010] Betamethasone epoxide is dissolved in toluene, stirred for reaction, and then boron trifluoride ether complex is added as a catalyst and HF aqueous solution is used for ring-opening fluorination reaction to obtain a reaction solution, and then the reaction solution is poured into ice water to precipitate a white solid, which is filtered to obtain a crude betamethasone product;

[0011] S2.1: Use HF aqueous solution as fluorination reagent and dissolve betamethasone epoxide in toluene;

[0012] S2.2: adding 130 to 132 parts by weight of boron trifluoride ether complex as a catalyst and HF aqueous solution at -25°C to -30°C to carry out fluorination reaction to obtain a reaction solution;

[0013] S2.3: The volume ratio of toluene to isopropanol was 5:1 by TLC. After TLC showed that the starting material disappeared, the reaction solution was poured into ice water to precipitate a white solid, which was filtered to obtain crude betamethasone;

[0014] S3: Preparation of polysorbate 80

[0015] Add a dehydration catalyst into sorbitol for catalytic reaction to obtain dehydrated sorbitol, then use dehydrated sorbitol and oleic acid as raw materials and add NaOH to obtain dehydrated sorbitan monooleate, then continuously add ethylene oxide to the dehydrated sorbitan monooleate for polyetherification reaction to obtain polysorbate 80;

[0016] S3.1: Compounding dilute sulfuric acid and p-toluenesulfonic acid in a mass ratio of (2.9-3.1):1 to obtain a compound as a dehydration catalyst;

[0017] S3.2: adding the dehydration catalyst obtained in step S2.1 to sorbitol for catalytic reaction, maintaining the temperature at 140°C to 143°C, and completing the reaction to obtain dehydrated sorbitol;

[0018] S3.3: Using sorbitan and oleic acid as raw materials, and using 0.3% to 0.5% NaOH as a catalyst, 0.3% to 0.5% NaOH is added dropwise to the raw materials, and reacted at 218° C. to 223° C. for 2 to 2.2 hours to obtain sorbitan monooleate;

[0019] S3.4: Continuously add ethylene oxide to sorbitan monooleate to carry out polyetherification reaction, add 0.3% to 0.5% sodium methoxide as a catalyst during the reaction, and after the reaction is completed, polysorbate 80 is obtained;

[0020] S4: Filtration of crude betamethasone

[0021] The crude betamethasone product is placed in a magnetic stirrer, and acetone is slowly added dropwise under magnetic stirring until the crude betamethasone product is dissolved, during which polysorbate 80 is added as a solubilizer to improve the solubility of the crude betamethasone product, and after the crude betamethasone product is completely dissolved, filtering is performed to obtain a filtrate;

[0022] S5: Recrystallized betamethasone

[0023] The filtrate is then continuously stirred, and during the stirring process, water is slowly added dropwise to the filtrate until solids are precipitated, and then the solution from which the solids are precipitated is filtered, and then washed with water to obtain betamethasone, and then the waste acetone in the waste solution obtained by filtration is distilled and collected, thereby recovering and reusing the acetone.

[0024] Furthermore, the preparation of boron trifluoride ether complex in step S1 specifically comprises the following steps:

[0025] S1.1: Add fuming sulfuric acid into a reaction kettle, slowly add crushed boric anhydride under stirring, the raw material mass ratio of boric anhydride to fuming sulfuric acid is 1:(2-2.2), react for 3-3.2 hours to prepare a sulfuric acid solution of acid anhydride;

[0026] S1.2: Stop stirring, cool to below 79°C to 83°C, add fluorite powder, the mass ratio of fluorite powder to boric anhydride is 1:(1.9-2.2);

[0027] S1.3: Then continue stirring and start heating. At 150℃~180℃, a large amount of boron trifluoride is produced with high purity. As the temperature rises, the gas volume gradually decreases.

[0028] S1.4: The generated boron trifluoride gas is subjected to gas phase complexation with the ether gas evaporated from the ether vaporizer in a complexation kettle;

[0029] S1.5: The complex product is a light yellow liquid with a boron trifluoride content of 45wt% to 48wt%. It is refined by distillation in a distiller and the fraction at 124°C to 126°C is the boron trifluoride ether complex. The ether recovered during the complexation and distillation process can be recycled in the complexation process.

[0030] Furthermore, the crude betamethasone filtration in step S4 specifically comprises the following steps:

[0031] S4.1: Place 4.9-5.3 parts by weight of crude betamethasone in a magnetic stirrer, and slowly add acetone dropwise at 22°C to 27°C under magnetic stirring until the crude betamethasone is dissolved;

[0032] S4.2: During the dissolution, polysorbate 80 is added as a solubilizer to increase the solubility of the crude betamethasone to obtain a mixed solution;

[0033] S4.3: After the crude betamethasone is completely dissolved, the mixed solution is filtered to obtain a filtrate.

[0034] Further, the recrystallization of betamethasone in step S5 specifically comprises the following steps:

[0035] S5.1: Add activated carbon into the waste solution for adsorption purification;

[0036] S5.2: filtering the waste solution and pre-treating the waste solution;

[0037] S5.3: The pretreated waste solution is then distilled and separated. The temperature during distillation is controlled at 56.5°C to 60°C, so that the acetone is vaporized and separated for recovery. The acetone obtained after distillation is reused.

[0038] Furthermore, when the boron trifluoride ether complex is added during the reaction in step S2, the addition rate of the boron trifluoride ether complex is controlled by an automatic titrator, and the dropping rate is 3 to 5 drops / s.

[0039] Furthermore, the amount of toluene used in step S2.1 is 5 to 6 times that of betamethasone epoxide.

[0040] Furthermore, the HF concentration in step S2 is 75% to 78%.

[0041] Furthermore, the mass ratio of sorbitan to oleic acid in S3.3 is 1:(1.5-2).

[0042] Compared with the prior art, the present invention has at least the following beneficial effects:

[0043] 1. The modified boron trifluoride ethyl ether is a boron trifluoride ethyl ether complex, which can improve the reaction activity and selectivity of boron trifluoride, reduce the corrosiveness of boron trifluoride ethyl ether to equipment, and improve the solubility and safety of boron trifluoride ethyl ether in solvents, and is beneficial to improve the yield of the ring-opening fluorination reaction of betamethasone epoxide, thereby improving the generation of the target product.

[0044] 2. Polysorbate 80 is used as a solubilizer. Dilute sulfuric acid and p-toluenesulfonic acid are compounded to obtain a dehydration catalyst. The dehydration catalyst is added into sorbitol for catalytic reaction to obtain dehydrated sorbitol. Dehydrated sorbitan and oleic acid are used as raw materials to prepare dehydrated sorbitan monooleate. Ethylene oxide is then added dropwise into the dehydrated sorbitan monooleate for polyetherification reaction to obtain polysorbate 80. The obtained polysorbate 80 is added dropwise into the dissolving crude betamethasone, which can improve the solubility of the crude betamethasone, thereby achieving the effect of improving the reaction rate and yield.

[0045] 3. Adding activated carbon into the waste acetone allows the activated carbon to adsorb the waste acetone, and then distilling the waste acetone to remove water from the waste acetone, and then recovering the acetone obtained after the distillation for reuse, thereby reducing the amount of wastewater discharged and saving the amount of acetone used. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The accompanying drawings, which are incorporated herein and constitute a part of the specification, illustrate embodiments of the present disclosure and, together with the description, further serve to explain the principles of the present disclosure and to enable those skilled in the relevant art to make and use the present disclosure.

[0047] Figure 1 The process flow chart of the preparation of betamethasone used in the embodiment of the present invention;

[0048] Figure 2 This is a summary table of experimental test results of Examples 1-3 of the present invention and Comparative Example 1.

[0049] Figure 3 This is a summary table of experimental test results of Examples 1-3 of the present invention and Comparative Example 2. DETAILED DESCRIPTION

[0050] The preparation process of betamethasone provided by the present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0051] Embodiment 1: a kind of preparation process of betamethasone, such as Figure 1 As shown, the following steps are included:

[0052] S1: Modify BF3OEt2 (boron trifluoride ethyl ether) to obtain boron trifluoride ethyl ether complex

[0053] S1.1: Add fuming sulfuric acid into a reaction kettle, slowly add crushed boric anhydride under stirring, the raw material mass ratio of boric anhydride to fuming sulfuric acid is 1:2, react for 3 hours to prepare a sulfuric acid solution of acid anhydride;

[0054] S1.2: Stop stirring, cool to below 81°C, add fluorite powder, the mass ratio of fluorite powder to boric anhydride is 1:2;

[0055] S1.3: Then continue stirring and start heating. At 160°C, a large amount of boron trifluoride (BF3) is produced with high purity. As the temperature rises, the gas volume gradually decreases.

[0056] S1.4: The generated boron trifluoride gas is subjected to gas phase complexation with the ether (C2H5)2O gas evaporated from the ether vaporizer in a complexing kettle;

[0057] S1.5: The complex product is a light yellow liquid with a boron trifluoride content of 47wt%. It is refined by distillation in a distiller and the fraction at 125°C is the boron trifluoride ether complex. The ether recovered during the complexation and distillation process can be recycled in the complexation process.

[0058] S2: Preparation of crude betamethasone

[0059] S2.1: Use HF aqueous solution as fluorination reagent and dissolve betamethasone epoxide in toluene;

[0060] S2.2: adding 130 parts by weight of boron trifluoride ether complex as a catalyst and HF aqueous solution at -26°C to carry out fluorination reaction, controlling the addition rate of the boron trifluoride ether complex by an automatic titrator at a dropping rate of 4 drops / s to obtain a reaction solution;

[0061] S2.3: The volume ratio of toluene and isopropanol was 5:1 by TLC. After TLC showed that the starting material disappeared, the reaction solution was poured into ice water to precipitate a white solid, which was filtered to obtain crude betamethasone.

[0062] S3: Preparation of polysorbate 80

[0063] S3.1: dilute sulfuric acid and p-toluenesulfonic acid are compounded in a mass ratio of 2.9:1 to obtain a compound as a dehydration catalyst;

[0064] S3.2: adding the dehydration catalyst obtained in step S2.1 to sorbitol for catalytic reaction, maintaining the temperature at 140° C., and completing the reaction to obtain dehydrated sorbitol;

[0065] S3.3: Using sorbitan and oleic acid as raw materials, and 0.3% NaOH as a catalyst, 0.3% NaOH is added dropwise to the raw materials, and the mixture is reacted at 220° C. for 2 hours to obtain sorbitan monooleate (Span-80);

[0066] S3.4: Continuously add ethylene oxide dropwise into sorbitan monooleate to carry out polyetherification reaction. During the reaction, 0.3% sodium methoxide is added as a catalyst. After the reaction is completed, polysorbate 80 is obtained.

[0067] S4: Filtration of crude betamethasone

[0068] S4.1: Place 5 parts by weight of crude betamethasone in a magnetic stirrer, and slowly add acetone dropwise under magnetic stirring at 22°C until the crude betamethasone is dissolved;

[0069] S4.2: During the dissolution, polysorbate 80 is added as a solubilizer to increase the solubility of the crude betamethasone to obtain a mixed solution;

[0070] S4.3: After the crude betamethasone is completely dissolved, the mixed solution is filtered to obtain a filtrate.

[0071] S5: Recrystallized Betamethasone

[0072] The filtrate is continuously stirred, and during the stirring process, water is slowly added to the filtrate until solids are precipitated, and then the solution with solid precipitation is filtered, and then washed with water to obtain betamethasone, and then the waste acetone in the waste solution obtained by filtration is distilled and recovered, and the steps are as follows:

[0073] S5.1: Add activated carbon into the waste solution for adsorption purification;

[0074] S5.2: filtering the waste solution and pre-treating the waste solution;

[0075] S5.3: The pretreated waste solution is then distilled and separated. The temperature during distillation is controlled at 60° C. to vaporize the acetone and separate it for recovery. The acetone obtained after distillation is reused.

[0076] When adding the boron trifluoride ether complex during the reaction in step S2, controlling the addition rate of the boron trifluoride ether complex helps maintain a stable reaction environment.

[0077] The amount of toluene used in step S2.1 is 5 times that of betamethasone epoxide.

[0078] The HF concentration in step S2 is 75%.

[0079] The mass ratio of sorbitan to oleic acid in S3.3 is 1:2.

[0080] Embodiment 2: A preparation process of betamethasone, such as Figure 1 As shown, the following steps are included:

[0081] S1: Modify BF3OEt2 (boron trifluoride ethyl ether) to obtain boron trifluoride ethyl ether complex

[0082] S1.1: Add fuming sulfuric acid into a reaction kettle, slowly add crushed boric anhydride under stirring, the raw material mass ratio of boric anhydride to fuming sulfuric acid is 1:2.1, react for 3 to 3.1 hours to prepare a sulfuric acid solution of acid anhydride;

[0083] S1.2: Stop stirring, cool to below 79°C to 83°C, add fluorite powder, the raw material mass ratio of fluorite powder to boric anhydride is 1:2.1;

[0084] S1.3: Then continue stirring and start heating. At 150℃~180℃, a large amount of boron trifluoride (BF3) is produced with high purity. As the temperature rises, the gas volume gradually decreases.

[0085] S1.4: The generated boron trifluoride gas is subjected to gas phase complexation with the ether (C2H5)2O gas evaporated from the ether vaporizer in a complexing kettle;

[0086] S1.5: The complex product is a light yellow liquid with a boron trifluoride content of 48wt%. It is refined by distillation in a distiller and the fraction at 124°C to 126°C is the boron trifluoride ether complex. The ether recovered during the complexation and distillation process can be recycled in the complexation process.

[0087] S2: Preparation of crude betamethasone

[0088] S2.1: Use HF aqueous solution as fluorination reagent and dissolve betamethasone epoxide in toluene;

[0089] S2.2: 132 parts by weight of boron trifluoride ether complex as a catalyst and HF aqueous solution are added at -25°C to -30°C to carry out fluorination reaction, and the addition rate of the boron trifluoride ether complex is controlled by an automatic titrator at a dropping rate of 3 to 5 drops / s to obtain a reaction solution;

[0090] S2.3: The volume ratio of toluene and isopropanol was 5:1 by TLC. After TLC showed that the starting material disappeared, the reaction solution was poured into ice water to precipitate a white solid, which was filtered to obtain crude betamethasone.

[0091] S3: Preparation of polysorbate 80

[0092] S3.1: dilute sulfuric acid and p-toluenesulfonic acid are compounded in a mass ratio of 3:1 to obtain a compound as a dehydration catalyst;

[0093] S3.2: adding the dehydration catalyst obtained in step S2.1 to sorbitol for catalytic reaction, maintaining the temperature at 140°C to 143°C, and completing the reaction to obtain dehydrated sorbitol;

[0094] S3.3: Using sorbitan and oleic acid as raw materials, and 0.4% NaOH as a catalyst, 0.4% NaOH is added dropwise to the raw materials, and the mixture is reacted at 218° C. to 223° C. for 2 to 2.1 hours to obtain sorbitan monooleate (Span-80);

[0095] S3.4: Continuously add ethylene oxide dropwise into sorbitan monooleate to carry out polyetherification reaction. During the reaction, 0.4% sodium methoxide is added as a catalyst. After the reaction is completed, polysorbate 80 is obtained.

[0096] S4: Filtration of crude betamethasone

[0097] S4.1: Place 5.3 parts by weight of crude betamethasone in a magnetic stirrer, and slowly add acetone dropwise at 22°C to 27°C under magnetic stirring until the crude betamethasone is dissolved;

[0098] S4.2: During the dissolution, polysorbate 80 is added as a solubilizer to increase the solubility of the crude betamethasone to obtain a mixed solution;

[0099] S4.3: After the crude betamethasone is completely dissolved, the mixed solution is filtered to obtain a filtrate.

[0100] S5: Recrystallized Betamethasone

[0101] The filtrate is continuously stirred, and during the stirring process, water is slowly added to the filtrate until solids are precipitated, and then the solution with solid precipitation is filtered, and then washed with water to obtain betamethasone, and then the waste acetone in the waste solution obtained by filtration is distilled and recovered, and the steps are as follows:

[0102] S5.1: Add activated carbon into the waste solution for adsorption purification;

[0103] S5.2: filtering the waste solution and pre-treating the waste solution;

[0104] S5.3: The pretreated waste solution is then distilled and separated. The temperature during distillation is controlled at 56.5°C to 60°C, so that the acetone is vaporized and separated for recovery. The acetone obtained after distillation is reused.

[0105] When adding the boron trifluoride ether complex during the reaction in step S2, controlling the addition rate of the boron trifluoride ether complex helps maintain a stable reaction environment.

[0106] The amount of toluene used in step S2.1 is 6 times that of betamethasone epoxide.

[0107] The HF concentration in step S2 was 76%.

[0108] The mass ratio of sorbitan to oleic acid in S3.3 is 1:1.5.

[0109] Embodiment 3: A preparation process of betamethasone, such as Figure 1 As shown, the following steps are included:

[0110] S1: Modify BF3OEt2 (boron trifluoride ethyl ether) to obtain boron trifluoride ethyl ether complex

[0111] S1.1: Add fuming sulfuric acid into a reaction kettle, slowly add crushed boric anhydride under stirring, the raw material mass ratio of boric anhydride to fuming sulfuric acid is 1:(2-2.2), react for 3.1 hours, and prepare a sulfuric acid solution of acid anhydride;

[0112] S1.2: Stop stirring, cool to below 83°C, add fluorite powder, the mass ratio of fluorite powder to boric anhydride is 1:(1.9-2.2);

[0113] S1.3: Then continue stirring and start heating. At 180°C, a large amount of boron trifluoride (BF3) is produced with high purity. As the temperature rises, the gas volume gradually decreases.

[0114] S1.4: The generated boron trifluoride gas is subjected to gas phase complexation with the ether (C2H5)2O gas evaporated from the ether vaporizer in a complexing kettle;

[0115] S1.5: The complex product is a light yellow liquid with a boron trifluoride content of 45wt%. It is refined by distillation in a distiller and the fraction at 126°C is the boron trifluoride ether complex. The ether recovered during the complexation and distillation process can be recycled in the complexation process.

[0116] S2: Preparation of crude betamethasone

[0117] S2.1: Use HF aqueous solution as fluorination reagent and dissolve betamethasone epoxide in toluene;

[0118] S2.2: adding 130 to 132 parts by weight of boron trifluoride ether complex as a catalyst and HF aqueous solution at -27°C to carry out fluorination reaction, controlling the addition rate of the boron trifluoride ether complex by an automatic titrator at a dropping rate of 3 drops / s to obtain a reaction solution;

[0119] S2.3: The volume ratio of toluene and isopropanol was 5:1 by TLC. After TLC showed that the starting material disappeared, the reaction solution was poured into ice water to precipitate a white solid, which was filtered to obtain crude betamethasone.

[0120] S3: Preparation of polysorbate 80

[0121] S3.1: Compounding dilute sulfuric acid and p-toluenesulfonic acid in a mass ratio of (2.9-3.1):1 to obtain a compound as a dehydration catalyst;

[0122] S3.2: adding the dehydration catalyst obtained in step S2.1 to sorbitol for catalytic reaction, maintaining the temperature at 141°C, and completing the reaction to obtain dehydrated sorbitol;

[0123] S3.3: Using sorbitan and oleic acid as raw materials, and using 0.3% to 0.5% NaOH as a catalyst, 0.3% to 0.5% NaOH is added dropwise to the raw materials, and reacted at 221° C. for 2.1 hours to obtain sorbitan monooleate (Span-80);

[0124] S3.4: Continuously add ethylene oxide dropwise into sorbitan monooleate to carry out polyetherification reaction. During the reaction, 0.3% to 0.5% sodium methoxide is added as a catalyst. After the reaction is completed, polysorbate 80 is obtained.

[0125] S4: Filtration of crude betamethasone

[0126] S4.1: Place 4.9-5.3 parts by weight of crude betamethasone in a magnetic stirrer, and slowly add acetone dropwise under magnetic stirring at 23°C until the crude betamethasone is dissolved;

[0127] S4.2: During the dissolution, polysorbate 80 is added as a solubilizer to increase the solubility of the crude betamethasone to obtain a mixed solution;

[0128] S4.3: After the crude betamethasone is completely dissolved, the mixed solution is filtered to obtain a filtrate.

[0129] S5: Recrystallized betamethasone

[0130] The filtrate is continuously stirred, and during the stirring process, water is slowly added to the filtrate until solids are precipitated, and then the solution with solid precipitation is filtered, and then washed with water to obtain betamethasone, and then the waste acetone in the waste solution obtained by filtration is distilled and recovered, and the steps are as follows:

[0131] S5.1: Add activated carbon into the waste solution for adsorption purification;

[0132] S5.2: filtering the waste solution and pre-treating the waste solution;

[0133] S5.3: The pretreated waste solution is then distilled and separated. The temperature during distillation is controlled at 59° C. to vaporize and separate the acetone for recovery. The acetone obtained after distillation is reused.

[0134] When adding the boron trifluoride ether complex during the reaction in step S2, controlling the addition rate of the boron trifluoride ether complex helps maintain a stable reaction environment.

[0135] The amount of toluene used in step S2.1 is 5 to 6 times that of betamethasone epoxide.

[0136] The HF concentration in step S2 is 75% to 78%.

[0137] The mass ratio of sorbitan to oleic acid in S3.3 is 1:(1.5-2).

[0138] Comparative Example 1:

[0139] Compared with Example 1, the difference of Comparative Example 1 is that the boron trifluoride etherate modification in step S1 is not performed, the boron trifluoride etherate complex is replaced with boron trifluoride etherate in step S2.2, and the other steps remain unchanged, specifically:

[0140] S2.1: Use HF aqueous solution as fluorination reagent and dissolve betamethasone epoxide in toluene;

[0141] S2.2: adding 130 parts by weight of boron trifluoride etherate as a catalyst and HF aqueous solution at -26°C to carry out fluorination reaction to obtain a reaction solution;

[0142] S2.3: The volume ratio of toluene to isopropanol was 5:1 during TLC. After TLC showed that the raw material disappeared, the reaction solution was poured into ice water to precipitate a white solid, which was filtered to obtain a crude betamethasone product. The obtained crude betamethasone product was recorded as Comparative Example 1.

[0143] Comparative Example 2:

[0144] Compared with Example 1, the difference of Comparative Example 2 is that steps S3 and S4.2 are removed, specifically:

[0145] S4.1: Place 5 parts by weight of crude betamethasone in a magnetic stirrer, and slowly add acetone dropwise under magnetic stirring at 22°C until the crude betamethasone is dissolved;

[0146] S4.3: After the crude betamethasone is completely dissolved, the mixed solution is filtered to obtain a filtrate. The obtained filtrate is recorded as Comparative Example 2.

[0147] The crude betamethasone product and the filtrate obtained in step S2 and step S4 of Example 1-3 are respectively recorded as Example 1-3.

[0148] Yield refers to the percentage of the desired product produced based on the amount of reactants. It is usually expressed as mass percentage or volume percentage.

[0149] Yield = (amount of target product produced / amount of reactants fed) × 100%.

[0150] The yield of betamethasone in Examples 1-3 can be calculated using the above formula and organized into a table, such as Figure 2 As shown, it can be seen that the product yield of Comparative Example 1 is lower than that of Examples 1-3 because the boron trifluoride ether complex can increase the reaction activity and improve the solubility. Therefore, the product yield of Comparative Example 1 is lower than that of the examples.

[0151] Yield = actual yield / theoretical yield.

[0152] The above formula can be used to calculate the yield of betamethasone in Examples 1-3 and organize them into a table, such as Figure 3 As shown, it can be seen that the yield of Comparative Example 2 is lower than that of the embodiment because polysorbate 80 can solubilize the crude betamethasone and increase the reaction rate and yield, so the product yield of Comparative Example 2 is lower than that of the embodiment.

[0153] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A process for preparing betamethasone, characterized in that: The steps include: S1: Preparation of Boron Trifluoride Ether Complex A quantitative amount of fuming sulfuric acid is added into a reaction kettle, and boric anhydride and fluorite powder are added and stirred to generate boron fluoride gas, and the boron fluoride gas is gas-phase complexed with ether gas evaporated from an ether vaporizer, and then distilled in a distiller to obtain a boron trifluoride ether complex; S2: Preparation of crude betamethasone Betamethasone epoxide is dissolved in toluene, stirred for reaction, and then boron trifluoride ether complex is added as a catalyst and HF aqueous solution is used for ring-opening fluorination reaction to obtain a reaction solution, and then the reaction solution is poured into ice water to precipitate a white solid, which is filtered to obtain a crude betamethasone product; S2.1: Use HF aqueous solution as fluorination reagent and dissolve betamethasone epoxide in toluene; S2.2: adding 130 to 132 parts by weight of boron trifluoride ether complex as a catalyst and HF aqueous solution at -25°C to -30°C to carry out fluorination reaction to obtain a reaction solution; S2.3: The volume ratio of toluene to isopropanol was 5:1 by TLC. After TLC showed that the starting material disappeared, the reaction solution was poured into ice water to precipitate a white solid, which was filtered to obtain crude betamethasone; S3: Preparation of polysorbate 80 Add a dehydration catalyst into sorbitol for catalytic reaction to obtain dehydrated sorbitol, then use dehydrated sorbitol and oleic acid as raw materials and add NaOH to obtain dehydrated sorbitan monooleate, then continuously add ethylene oxide to the dehydrated sorbitan monooleate for polyetherification reaction to obtain polysorbate 80; S3.1: Compounding dilute sulfuric acid and p-toluenesulfonic acid in a mass ratio of (2.9-3.1):1 to obtain a compound as a dehydration catalyst; S3.2: adding the dehydration catalyst obtained in step S2.1 to sorbitol for catalytic reaction, maintaining the temperature at 140°C to 143°C, and completing the reaction to obtain dehydrated sorbitol; S3.3: Using sorbitan and oleic acid as raw materials, and using 0.3% to 0.5% NaOH as a catalyst, 0.3% to 0.5% NaOH is added dropwise to the raw materials, and reacted at 218° C. to 223° C. for 2 to 2.2 hours to obtain sorbitan monooleate; S3.4: Continuously add ethylene oxide to sorbitan monooleate to carry out polyetherification reaction, add 0.3% to 0.5% sodium methoxide as a catalyst during the reaction, and after the reaction is completed, polysorbate 80 is obtained; S4: Filtration of crude betamethasone The crude betamethasone product is placed in a magnetic stirrer, and acetone is slowly added dropwise under magnetic stirring until the crude betamethasone product is dissolved, during which polysorbate 80 is added as a solubilizer to improve the solubility of the crude betamethasone product, and after the crude betamethasone product is completely dissolved, filtering is performed to obtain a filtrate; S4.1: Place 4.9-5.3 parts by weight of crude betamethasone in a magnetic stirrer, and slowly add acetone dropwise at 22°C to 27°C under magnetic stirring until the crude betamethasone is dissolved; S4.2: During the dissolution, polysorbate 80 is added as a solubilizer to increase the solubility of the crude betamethasone to obtain a mixed solution; S4.3: After the crude betamethasone is completely dissolved, the mixed solution is filtered to obtain a filtrate; S5: Recrystallized betamethasone The filtrate is then continuously stirred, and during the stirring process, water is slowly added dropwise to the filtrate until solids are precipitated, and then the solution from which the solids are precipitated is filtered, and then washed with water to obtain betamethasone, and then the waste acetone in the waste solution obtained by filtration is distilled and collected, thereby recovering and reusing the acetone.

2. The preparation process of betamethasone according to claim 1, characterized in that: The preparation of boron trifluoride ether complex in step S1 specifically comprises the following steps: S1.1: Add fuming sulfuric acid into a reaction kettle, slowly add crushed boric anhydride under stirring, the raw material mass ratio of boric anhydride to fuming sulfuric acid is 1:(2-2.2), react for 3-3.2 hours to prepare a sulfuric acid solution of acid anhydride; S1.2: Stop stirring, cool to below 79°C to 83°C, add fluorite powder, the mass ratio of fluorite powder to boric anhydride is 1:(1.9-2.2); S1.3: Then continue stirring and start heating. At 150℃~180℃, a large amount of boron trifluoride is produced with high purity. As the temperature rises, the gas volume gradually decreases. S1.4: The generated boron trifluoride gas is subjected to gas phase complexation with the ether gas evaporated from the ether vaporizer in a complexation kettle; S1.5: The complex product is a light yellow liquid with a boron trifluoride content of 45wt% to 48wt%. It is refined by distillation in a distiller and the fraction at 124°C to 126°C is the boron trifluoride ether complex. The ether recovered during the complexation and distillation process can be recycled in the complexation process.

3. The preparation process of betamethasone according to claim 2, characterized in that, The preparation of crude betamethasone in step S2 specifically comprises the following steps: S2.1: Use HF aqueous solution as fluorination reagent and dissolve betamethasone epoxide in toluene; S2.2: adding 130 to 132 parts by weight of boron trifluoride ether complex as a catalyst and HF aqueous solution at -25°C to -30°C to carry out fluorination reaction to obtain a reaction solution; S2.3: The volume ratio of toluene and isopropanol was 5:1 by TLC. After TLC showed that the starting material disappeared, the reaction solution was poured into ice water to precipitate a white solid, which was filtered to obtain crude betamethasone.

4. The preparation process of betamethasone according to claim 3, characterized in that: The recrystallization of betamethasone in step S5 specifically comprises the following steps: S5.1: Add activated carbon into the waste solution for adsorption purification; S5.2: filtering the waste solution and pre-treating the waste solution; S5.3: The pretreated waste solution is then distilled and separated. The temperature during distillation is controlled at 56.5°C to 60°C, so that the acetone is vaporized and separated for recovery. The acetone obtained after distillation is reused.

5. The preparation process of betamethasone according to claim 4, characterized in that: When the boron trifluoride ether complex is added during the reaction in step S2, the addition rate of the boron trifluoride ether complex is controlled by an automatic titrator, and the dropping rate is 3 to 5 drops / s.

6. The process for preparing betamethasone according to claim 5, characterized in that: The amount of toluene used in step S2.1 is 5 to 6 times that of betamethasone epoxide.

7. The process for preparing betamethasone according to claim 6, characterized in that: The HF concentration in step S2 is 75% to 78%.

8. The process for preparing betamethasone according to claim 7, characterized in that: The mass ratio of sorbitan to oleic acid in S3.3 is 1:(1.5-2).

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