A method for the synthesis of budesonide

Abstract

This invention relates to the field of pharmaceutical chemical synthesis technology, and in particular to a method for synthesizing budesonide, comprising the following steps: under alkaline conditions, using a compound of formula (1) as a raw material, a substitution reaction is performed to obtain a compound of formula (2); under alkaline conditions, a sulfonation reaction is performed on compound (2) to obtain a compound of formula (3); under acidic conditions, a esterification reaction is performed on compound (3) to obtain a compound of formula (4); under alkaline conditions, a reduction reaction is performed on compound (4) to obtain a compound of formula (5); under acidic conditions, a oxidation reaction is performed on compound (5) to obtain a compound of formula (6); under alkaline conditions, a hydrolysis reaction is performed on compound (6) to obtain a compound of formula (7); under acidic conditions, a condensation reaction is performed on compound (7) to obtain budesonide. This invention achieves high efficiency, economy, and environmental friendliness in the synthesis of budesonide through step integration, reagent optimization, and green purification.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, and in particular to a method for synthesizing budesonide. Background Technology

[0002] Budesonide, developed and marketed by AstraZeneca in 1981, has the chemical name 16α,17α-22R,S-propylmethylenedioxy-pregn-1,4-diene-11b,21-dihydroxy-3,20-dione, ethoxy-17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid-γ-lactone. It is a non-halogenated glucocorticoid with strong anti-inflammatory effects, capable of inhibiting early bronchospasm and late-stage allergic reactions. Primarily used for the treatment of asthma or allergic rhinitis, it is the first-line drug in clinical practice for treating asthma with aerosols and nasal allergies. Its mechanism of action involves stimulating β2-adrenergic receptors, increasing intracellular cyclic adenosine monophosphate (cAMP), thereby relaxing smooth muscle and achieving bronchodilation. Simultaneously, as a glucocorticoid, budesonide can inhibit the production of inflammatory mediators such as leukotrienes, thus exerting an anti-inflammatory effect. Budenet's structural formula is as follows:

[0003] There are already relevant patents and literature reports on the synthesis of budesonide both domestically and internationally. In summary, there are two main synthetic routes: semi-biological synthesis and chemical synthesis.

[0004] Regarding the semi-biosynthesis method, US Patent 3536586 discloses a method for synthesizing budesonide using hydrocortisone as a starting material and employing microbial strains. However, the semi-biosynthesis method is complex due to the complexity of the products of oxidative dehydrogenation. The use of microbial strains often requires continuous multi-stage countercurrent extraction and separation, which makes the process complex, cumbersome, and requires high technical and equipment standards. Moreover, there are technical bottlenecks in the source, screening, and preservation of microbial strains, making it difficult to achieve large-scale production.

[0005] Regarding the chemical synthesis method, WO87 / 05028 discloses a method for synthesizing budesonide by using prednisolone acetate as a starting material and proceeding through esterification, reduction, elimination, oxidation, condensation, and hydrolysis reactions. This method uses expensive starting materials, and the osmium tetroxide used poses a significant hazard to operators. Furthermore, the reduction of the 11-keto group generates an 11α-hydroxy byproduct, making product purification difficult and resulting in a total yield of only 5%, which is too low.

[0006] WO92 / 11280 discloses a method for synthesizing budesonide from prednisone as a starting material through cyclization, ring opening, esterification, elimination, oxidation, condensation, and hydrolysis. This method uses expensive starting materials, and the 21-hydroxyl group also undergoes esterification during the cyclization process, producing diesters (esterification at both the 17 and 21 positions). Furthermore, the reduction of the ketone group at the 11 position also produces 11α-hydroxyl byproducts, making product purification difficult and resulting in a low overall yield of about 20%.

[0007] Chinese patent CN101279997A discloses a method for synthesizing budesonide using prednisolone acetate as a starting material through elimination, oxidation, reduction, hydrolysis, and condensation reactions. This method uses expensive starting materials, and the high concentrations of hydrogen peroxide used (60%, 70%, 80%, and 90%) easily decompose into oxygen, posing a significant safety hazard. Furthermore, the reduction of the 11-keto group also produces 11α-hydroxy byproducts, making product purification difficult. Therefore, this method is not suitable for industrial production.

[0008] Chinese patent CN111560047A discloses a method for synthesizing budesonide using prednisolone acetate as a starting material, through protection, dehydration, dihydroxylation, hydrolysis, and condensation reactions. This method uses expensive starting materials, and the trifluoroacetic anhydride and pyridine used are highly toxic to the aquatic environment. The dehydration reaction requires harsh conditions (-40~-10℃) and demanding equipment. Furthermore, during the dehydration reaction, under the strongly acidic conditions of sulfur dioxide, the 17-hydroxyl group undergoes self-dehydration to form an ether, leading to incomplete substrate reaction, making product purification difficult and resulting in low yield. Additionally, during the elimination reaction, due to the strong negative charge effect of fluorine, when the 17-hydroxyl group undergoes elimination, the 11-trifluoroacetate also undergoes overall elimination, forming byproducts 9 and 11 double bond impurities, further complicating product purification and resulting in low yield.

[0009] In view of this, the present invention is proposed. Summary of the Invention

[0010] The purpose of this invention is to provide a method for synthesizing budesonide, which features inexpensive and readily available raw materials, low cost, mild reaction conditions, environmental friendliness, shortened reaction steps, high synthesis efficiency, high product yield and purity, and simple process operation, making it suitable for industrialization.

[0011] This invention provides a method for synthesizing budesonide, comprising the following steps: S1. Under alkaline conditions, using the compound of formula (1) as a raw material, the compound of formula (2) is obtained through a displacement reaction; S2. Under alkaline conditions, compound (2) is sulfonated to obtain compound (3); S3. Under acidic conditions, the compound of formula (3) undergoes an esterification reaction to obtain the compound of formula (4); S4. Under alkaline conditions, compound (4) undergoes an elimination reaction to obtain compound (5); S5. Under acidic conditions, compound (5) undergoes an oxidation reaction to obtain compound (6); S6. Under alkaline conditions, the compound of formula (6) undergoes a hydrolysis reaction to obtain the compound of formula (7); S7. Under acidic conditions, the compound of formula (7) undergoes a condensation reaction to obtain budesonide of formula (8); The reaction process is as follows: .

[0012] In this invention, step S1 uses a 21-chloropregnane derivative as the starting material and directly introduces the ester group by substitution with a carboxylate (such as potassium acetate or ethyl acetate) under alkaline conditions. Compared with the traditional method that requires multiple steps to construct the 21-position ester group (such as oxidation followed by esterification), the reaction raw materials are inexpensive and the cost is low. It avoids the separation of intermediates, improves the overall yield, and the reaction conditions are mild, without the need for strong oxidants or high temperature and pressure. Step S2 uses a 21-ester-substituted compound of formula (2) as the starting material. Its hydroxyl group reacts with methanesulfonyl chloride under alkaline conditions to generate sulfonate esters (-OMs). As a protecting group, methanesulfonyl chloride has high selectivity and only reacts with the hydroxyl group, without affecting other sensitive groups. The generated -OMs can not only temporarily protect the hydroxyl group and prevent it from being destroyed in subsequent steps, but also -OMs have a lower electronegativity than trifluoroacetate and are excellent leaving groups, which facilitates the subsequent elimination reaction (step S4). This avoids the byproducts of the 9 and 11 double bond impurities during the 11-position elimination reaction in (step S4), which facilitates subsequent separation and purification. In step S3, the hydroxyl group at position 17 of compound (3) condenses with carboxylic acid / anhydride under acid catalysis, providing a key intermediate for the elimination reaction in step S4. The elimination reaction in step S4 involves the hydroxyl group at position 17 first forming an acetate ester with acetic anhydride, followed by an elimination reaction under alkaline conditions. This avoids the formation of the byproduct 17-ether compound through dehydration of the hydroxyl group itself, ensuring complete reaction of the raw materials and high purity of the resulting product. Step S5 achieves olefin cleavage and selective oxidation of the hydroxyl group through oxidation under acidic conditions with potassium permanganate, avoiding the environmental risk of OsO4. This step is efficient, economical, conforms to green chemistry principles, and provides a key intermediate for subsequent hydrolysis (step S6) and condensation (step S7). Step S6 involves simultaneous alkaline hydrolysis, removing the ester group at position 21 and the methanesulfonyl ester at position 11 in one step, efficiently generating the intermediates of 21-carboxylic acid and 11-hydroxyl. Step S7 constructs the key 16α,17α-ketal structure of budesonide through acid-catalyzed condensation reaction, and achieves high yield and high purity by crystallization using a mixed solvent of acetone / isopropyl ether.

[0013] Therefore, this invention has the advantages of using inexpensive and readily available raw materials, resulting in low cost; mild reaction conditions, making it environmentally friendly; shortened reaction steps, resulting in high synthesis efficiency; high product yield and high purity; and simple process operation, making it suitable for industrialization.

[0014] As a preferred embodiment of this technical solution, in step S1, during the displacement reaction, The solvents used include any one or more combinations of ethyl acetate, toluene, acetone, tetrahydrofuran, dichloromethane, dioxane, and N,N-dimethylformamide. Polar aprotic solvents are preferred for nucleophilic substitution reactions (SN2) to avoid solvation of nucleophiles by protic solvents.

[0015] The alkali used includes any one or more combinations of potassium carbonate, potassium acetate, potassium hydroxide, potassium ethoxide, sodium carbonate, sodium acetate, sodium hydroxide, and sodium ethoxide, and is preferably potassium acetate and sodium acetate. The amount of solvent required for each 1 g of compound (1) is 1 to 10 mL, preferably 2 to 5 mL, and the amount of base required for each 1 g of compound (1) is 0.1 to 5 g, preferably 0.2 to 1.2 g. The relative excess of base can ensure the concentration of carboxylate ions, thereby promoting the complete reaction. During the displacement reaction, the temperature is controlled at 45–105 °C, preferably 65–95 °C, and the time is 1–10 h, preferably 3–6 h. Increasing the temperature can accelerate the reaction, but side reactions, such as elimination reactions, must be avoided.

[0016] As a preferred embodiment of this technical solution, in step S1, after the displacement reaction is completed, water is added to terminate the reaction, the mixture is concentrated to dryness, cooled, filtered, and dried to obtain compound (2).

[0017] As a preferred embodiment of this technical solution, in step S2, during the sulfonation reaction, The solvents used include any one or more combinations of acetone, dichloromethane, toluene, and cyclohexane. The bases used include any one or more combinations of sodium methoxide, pyridine, diethylamine, triethylamine, and morpholine. The sulfonating agent used is methanesulfonyl chloride or its salt, or a derivative thereof. The amount of solvent required for each 1 g of compound (2) is 1 to 10 mL, preferably 6 to 8 mL; the amount of base required for each 1 g of compound (2) is 0.5 to 5 mL, preferably 1 to 3 mL; and the amount of sulfonating agent required for each 1 g of compound (2) is 0.3 to 3 mL, preferably 0.3 to 1 mL. During the sulfonation reaction, the temperature is controlled at -20 to 30°C, preferably 20 to 30°C. The reaction conditions are mild, and the reaction can be carried out at room temperature. No high-temperature or high-pressure equipment is required, which reduces the production cost. The reaction time is 1 to 10 hours, preferably 2 to 4 hours.

[0018] As a preferred embodiment of this technical solution, in step S2, after the sulfonation reaction is completed, water is added to terminate the reaction, the pH value is adjusted to 5-9, the layers are separated, the organic layer is washed with water, the organic layer is concentrated to dryness, cooled, filtered, and dried to obtain compound (3).

[0019] As a preferred embodiment of this technical solution, in step S3, during the esterification reaction, The solvents used include any one or more combinations of toluene, acetic acid, and dichloromethane; The acid and / or anhydride used includes any one or more combinations of acetic acid, acetic anhydride, concentrated sulfuric acid, phosphoric acid, hydrochloric acid, and p-toluenesulfonic acid. The amount of solvent required for each 1 g of compound (3) is 1 to 10 mL, preferably 2 to 4 mL, and the amount of acid / or anhydride required for each 1 g of compound (3) is 0.1 to 3 g, preferably 0.1 to 1 g. During the esterification reaction, the temperature is controlled at 60–120°C, preferably 80–100°C, and the time is 2–8 h, preferably 3–5 h.

[0020] As a preferred embodiment of this technical solution, in step S3, after the esterification reaction is completed, water is added for precipitation, the temperature is lowered, the mixture is filtered, and the product is dried to obtain the compound of formula (4).

[0021] As a preferred embodiment of this technical solution, in step S4, during the elimination reaction, The solvents used include any one or more combinations of toluene, acetone, dichloromethane, and N,N-dimethylformamide; The alkali used includes any one or more combinations of potassium hydroxide, potassium carbonate, potassium acetate, and sodium carbonate; The amount of solvent required for each 1 g of compound (4) is 7 to 12 mL, preferably 9 to 11 mL, and the amount of base required for each 1 g of compound (4) is 0.2 to 2 g, preferably 0.4 to 0.8 g. During the elimination reaction, the temperature is controlled at 30–80 °C, preferably 50–60 °C, and the time is 5–15 h, preferably 7–9 h.

[0022] As a preferred embodiment of this technical solution, in step S4, after the elimination reaction is completed, the mixture is concentrated to dryness, water is added for precipitation, the temperature is lowered, the mixture is filtered, and the mixture is dried to obtain compound (5).

[0023] As a preferred embodiment of this technical solution, in step S5, during the oxidation reaction, The solvents used include any one or more combinations of toluene, acetone, and dichloromethane; The acids used include any one or more combinations of formic acid, concentrated sulfuric acid, glacial acetic acid, and phosphoric acid; The oxidizing agents used include any one or more combinations of sodium hypochlorite, potassium permanganate, chromic anhydride, and manganese dioxide. The amount of solvent required for each 1g of compound (5) is 20-70mL, preferably 40-60mL; the amount of acid required for each 1g of compound (5) is 0.1-1g, preferably 0.3-0.6g; and the amount of oxidant required for each 1g of compound (5) is 0.2-2g, preferably 0.5-1g. During the oxidation reaction, the temperature is controlled at 0–50°C, preferably 20–30°C, and the time is 1–5 h, preferably 1–3 h.

[0024] As a preferred embodiment of this technical solution, in step S5, after the oxidation reaction is completed, an aqueous solution of concentrated sodium sulfite is added to terminate the reaction, the mixture is filtered, the filtrate is concentrated to dryness, cooled, filtered, and dried to obtain the compound of formula (6).

[0025] As a preferred embodiment of this technical solution, in step S6, during the hydrolysis reaction, The solvents used include any one or more combinations of toluene, methanol, acetone, and dichloromethane. The alkali used includes any one or more combinations of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium acetate. The amount of solvent required for each 1g of compound (6) is 5 to 15 mL, preferably 11 to 14 mL, and the amount of base required for each 1g of compound (6) is 0.01 to 0.1 g, preferably 0.01 to 0.05 g. During the hydrolysis reaction, the temperature is controlled at -30 to 30°C, preferably -20 to 0°C, and the time is 1 to 5 hours, preferably 2 to 3 hours.

[0026] As a preferred embodiment of this technical solution, in step S6, after the hydrolysis reaction is completed, the pH value is adjusted to 6-8, the reaction solution is concentrated to dryness, cooled, filtered, and dried to obtain compound (7).

[0027] As a preferred embodiment of this technical solution, in step S7, during the condensation reaction, The solvents used include any one or more combinations of N,N-dimethylformamide, acetonitrile, acetone, dichloromethane, and chloroform. The acids used include any one or more combinations of hydrochloric acid, p-toluenesulfonic acid, phosphoric acid, and perchloric acid. The condensing agent used is n-butyraldehyde. The amount of solvent required for each 1 g of compound (7) is 10 to 60 mL, preferably 10 to 30 mL; the amount of acid required for each 1 g of compound (7) is 1 to 10 mL, preferably 5 to 9 mL; and the amount of condensing reagent required for each 1 g of compound (7) is 0.2 to 2 mL, preferably 0.3 to 0.6 mL. During the condensation reaction, the temperature is controlled at 0–50 °C, preferably at 20–40 °C, and the time is 3–5 h.

[0028] As a preferred embodiment of this technical solution, in step S7, after the condensation reaction is completed, water is added to terminate the reaction, the organic phase is concentrated to dryness under reduced pressure, ethyl acetate is added, water is added again, the layers are separated, the aqueous layer is extracted with ethyl acetate, the organic phases are combined, the resulting extract is dried and filtered with anhydrous sodium sulfate, then ethyl acetate is concentrated to dryness, a mixed solvent of acetone and isopropyl ether is added for gradient cooling and crystallization, and after filtration and drying, budesonide of formula (8) is obtained.

[0029] As a preferred embodiment of this technical solution, during the gradient cooling process, the temperature is first lowered to 0-5°C, stirred for 1-3 hours, and then further lowered to -5-0°C, stirred overnight.

[0030] As a preferred embodiment of this technical solution, the volume ratio of acetone to isopropyl ether in the mixed solvent of acetone and isopropyl ether is 1:1.

[0031] The implementation of this invention has at least the following beneficial effects: 1. This invention uses 21-chloropregnane derivatives as starting materials and directly introduces ester groups by substitution with carboxylates (such as potassium acetate or ethyl acetate) under alkaline conditions. Compared with traditional methods that require multiple steps to construct 21-position ester groups (such as oxidation followed by esterification), this invention shortens the reaction steps, avoids intermediate separation, improves the overall yield, and the reaction conditions are mild, requiring no strong oxidants or high temperature and pressure. 2. In the sulfonation reaction, methanesulfonyl chloride is used as a protecting group. Methanesulfonyl chloride has high selectivity and only reacts with hydroxyl groups without affecting other sensitive groups. The generated -OMs can not only temporarily protect the hydroxyl groups and prevent them from being destroyed in subsequent steps, but also have lower electronegativity than trifluoroacetate, making them excellent leaving groups. This facilitates the subsequent elimination reaction (step S4) and avoids the byproducts of the 9 and 11 double bond impurities during the 11-position elimination reaction in (step S4). This facilitates subsequent separation and purification. In addition, the reaction can be carried out at room temperature and has low requirements for reaction equipment. 3. In the elimination reaction, the 17-hydroxyl group of this invention first forms an acetate ester with acetic anhydride, and then the elimination reaction occurs in an alkaline environment. This avoids the formation of the by-product 17-ether compound by dehydration of the 17-hydroxyl group itself. The raw materials react completely and the product obtained has high purity. 4. In the oxidation reaction, the present invention achieves olefin cleavage and selective oxidation of hydroxyl groups through oxidation under acidic conditions of potassium permanganate, avoiding the environmental risks of OsO4. This step is efficient and economical, conforms to the principles of green chemistry, and provides key intermediates for subsequent hydrolysis (step S6) and condensation (step S7). 5. This invention removes the ester group at position 21 and the methanesulfonyl ester at position 11 in one step through alkaline simultaneous hydrolysis, efficiently generating 21-carboxylic acid and 11-hydroxy intermediates, thus shortening the reaction steps. 6. This invention constructs the key 16α,17α-ketal structure of budesonide through acid-catalyzed condensation reaction, and achieves high yield and high purity by crystallization using a mixed solvent of acetone / isopropyl ether. Studies have shown that the yield of the obtained product can reach more than 70%, and the purity can reach more than 99.5%. Attached Figure Description

[0032] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0033] Figure 1 The TLC layer diagrams of the 11-position protective material obtained in Embodiment 1 and Comparative Example 1 of the present invention are shown. Figure 2 The HPLC chromatogram of budesonide, the product obtained in this invention, is shown below. Figure 3 The TLC layer diagrams are of the eliminators obtained in Example 1 and Comparative Example 3 of the present invention. Detailed Implementation

[0034] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0035] It should be noted that the terminology used herein is for the purpose of describing particular implementations only and is not intended to limit the exemplary implementations according to this application. As used herein, the singular form includes the plural form unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this description, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0036] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] The raw materials (compound of formula (1)) used in this invention can be purchased directly as finished products or made in-house. This invention uses 9-hydroxy-AD as the starting material and prepares compound of formula (1) through four steps: cyanation reaction, etherification reaction, transposition reaction, and dehydrogenation reaction. The following are the reaction equations involved in the preparation process of compound of formula (1) used in the embodiments of this invention. For specific reaction details, please refer to the prior art. They will not be repeated here.

[0038]

[0039] Example 1 S1, Displacement reaction: In a clean reaction flask, add 50 g of compound (1), 200 mL of DMF and 20 g of potassium acetate, stir for 0.5 h, then heat to 75-80 ℃, keep the temperature at 75-80 ℃ for 4-5 hours. After the reaction is complete, add 500 mL of water to the reaction solution, cool, filter, and dry to obtain 49.8 g of compound (2); S2, sulfonation reaction: In a clean reaction flask, add 49.8 g of compound (2), 300 mL of dichloromethane and 100 mL of diethylamine, cool to 25 °C, add 40 mL of methanesulfonyl chloride, and keep the reaction at 20-25 °C for 2.5-3.5 h. After the reaction is complete, add 200 mL of water to the reaction solution, adjust the pH to 5-9 with hydrochloric acid, separate the layers, extract the aqueous layer with dichloromethane, combine the organic layers, concentrate the organic layer under reduced pressure to dryness, cool, filter, and dry to obtain 48.8 g of compound (3); S3, Esterification reaction: In a clean reaction flask, add 48.8 g of compound (3), 180 mL of toluene, and 5 g of concentrated sulfuric acid. Heat to 90-100 °C and keep at 90-100 °C for 4-5 h. After the reaction is complete, add 10 mL of water to terminate the reaction. Concentrate under reduced pressure to dryness, cool, filter, and dry to obtain 47.9 g of compound (4). S4. Elimination reaction: In a clean reaction flask, add 47.9 g of compound (4), 450 mL of DMF and 30 g of potassium carbonate, heat to 50-60 °C, and keep the temperature at 50-60 °C for 7.5-8.5 h. After the reaction is complete, concentrate under reduced pressure to dryness, add water to precipitate, cool, filter, and dry to obtain 47.1 g of compound (5). S5. Oxidation reaction: In a clean reaction flask, add 47.1 g of compound (5), 2400 mL of acetone, 20 g of formic acid, 120 mL of water and 30 g of potassium permanganate. Keep the reaction at 20-25 °C for 1.5-2.5 h. After the reaction is complete, add sodium sulfite aqueous solution to terminate the reaction, filter, concentrate the filtrate under reduced pressure to dryness, cool, filter, and dry to obtain 46.6 g of compound (6). S6. Hydrolysis reaction: In a clean reaction flask, add 46.6 g of compound (6), 375 mL of methanol and 233 mL of dichloromethane, cool to -10 to -5 ℃, add 6 g of sodium hydroxide aqueous solution (2 g of sodium hydroxide dissolved in 4 g of water) dropwise, the dropwise addition time is about 0.5 to 1 h, after the dropwise addition is completed, keep the reaction at -10 to -5 ℃ for 2 to 3 h, after the reaction is completed, adjust the pH to 6 to 8 with glacial acetic acid, concentrate the reaction solution to dryness, cool, filter, dry, and obtain 42.4 g of compound (7); S7. Condensation reaction: In a clean reaction flask, add 750 mL of dichloromethane, 42.4 g of compound (7) and 0.8 g of PTS, stir for 0.5 h, add 30 mL of n-butyraldehyde dropwise at room temperature, and after the addition is complete, keep the reaction at 20-30 ℃ for 2-3 h. After the reaction is complete, add 100 mL of water to terminate the reaction, separate the layers, concentrate the organic phase to dryness under reduced pressure, add 750 mL of ethyl acetate, add 200 mL of water, separate the layers, extract the aqueous layer with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add 25 mL of acetone and 25 mL of isopropyl ether, stir for 2 h, cool to 0-5 ℃, stir for 2 h, continue to cool to -5-0 ℃, stir overnight, filter and dry to obtain 36.5 g of budesonide.

[0040] The yield of budesonide obtained in this example was 73%, and the HPLC content was 99.7%. Figure 1 This is the HPLC chromatogram of budesonide obtained in this embodiment.

[0041] Example 2 S1, Displacement reaction: In a clean reaction flask, add 50 g of compound (1), 250 mL of ethyl acetate, and 25 g of potassium acetate, stir for 0.5 h, then heat to 75-80 ℃, keep the temperature at 75-80 ℃ for 4-5 h, after the reaction is complete, concentrate to dryness under reduced pressure, add 5 mL of water to the reaction solution, cool, filter, and dry to obtain 49.5 g of compound (2); S2, sulfonation reaction: In a clean reaction flask, add 49.5 g of compound (2), 450 mL of toluene and 100 mL of pyridine, cool to 25 °C, add 40 mL of methanesulfonyl chloride, and keep the reaction at 25-30 °C for 2.5-3.5 h. After the reaction is complete, add 200 mL of water to the reaction solution, adjust the pH to 5-9 with hydrochloric acid, separate the layers, extract the aqueous layer with dichloromethane, combine the organic layers, concentrate under reduced pressure to dryness, cool, filter, and dry to obtain 48.1 g of compound (3); S3, Esterification reaction: In a clean reaction flask, add 48.1 g of compound (3), 180 mL of toluene and 10 g of p-toluenesulfonic acid, heat to 90-100 ℃, keep at 90-100 ℃ for 4-5 h, after the reaction is complete, add 10 mL of water to stop the reaction, concentrate under reduced pressure to dryness, cool, filter, and dry to obtain 47.4 g of compound (4); S4. Elimination reaction: In a clean reaction flask, add 47.4 g of compound (4), 475 mL of toluene and 25 g of potassium acetate, heat to 50-60 °C, and keep the temperature at 50-60 °C for 7.5-8.5 h. After the reaction is complete, concentrate under reduced pressure to dryness, add water to precipitate, cool, filter, and dry to obtain 46.7 g of compound (5). S5. Oxidation reaction: In a clean reaction flask, add 46.7 g of compound (5), 2400 mL of acetone, 20 g of formic acid, 100 mL of water and 30 g of potassium permanganate. Keep the reaction at 25-30 °C for 1.5-2.5 h. After the reaction is complete, add sodium thiosulfate aqueous solution to terminate the reaction. Filter, concentrate the filtrate under reduced pressure to dryness, cool, filter, and dry to obtain 46.6 g of compound (6). S6. Hydrolysis reaction: In a clean reaction flask, add 46.6 g of compound (6), 375 mL of methanol and 233 mL of dichloromethane, cool to -10 to -5 ℃, add 4.2 g of potassium hydroxide aqueous solution (1.4 g of potassium hydroxide dissolved in 2.8 g of water) dropwise, the dropwise addition time is about 0.5 to 1 h, after the dropwise addition is completed, keep the reaction at -20 to -10 ℃ for 2 to 3 h, after the reaction is completed, adjust the pH to 6 to 8 with glacial acetic acid, concentrate the reaction solution to dryness, cool, filter, dry, and obtain 41.5 g of compound (7); S7. Condensation reaction: In a clean reaction flask, add 500 mL of DMF, 41.5 g of compound (7), and 200 mL of 70% perchloric acid. Stir for 0.5 h, add 30 mL of n-butyraldehyde dropwise at room temperature. After the addition is complete, keep the reaction at 20-30 ℃ for 2-3 h. After the reaction is complete, add 100 mL of water to terminate the reaction. Concentrate the organic phase to dryness under reduced pressure, add 750 mL of ethyl acetate, and then add 200 mL of water. Separate the layers. Extract the aqueous layer with ethyl acetate. Combine the organic phases and dry them with anhydrous sodium sulfate. Filter the solution and concentrate the filtrate to dryness. Add 25 mL of acetone and 25 mL of isopropyl ether. Stir for 2 h, cool to 0-5 ℃, stir for 2 h, continue to cool to -5-0 ℃, stir overnight, filter and dry to obtain 35.3 g of budesonide.

[0042] The yield of budesonide obtained in this example was 70.6%, and the HPLC content was 99.6%.

[0043] Example 3 S1, Displacement reaction: In a clean reaction flask, add 50 g of compound (1), 200 mL of acetone and 30 g of sodium acetate, stir for 0.5 h, then heat to 75-80 ℃, keep the temperature at 75-80 ℃ for 4-5 hours, after the reaction is complete, add 500 mL of water to the reaction solution, cool, filter, dry, and obtain 48.9 g of compound (2); S2, sulfonation reaction: In a clean reaction flask, add 48.9g of compound (2), 400 mL of toluene and 100 mL of triethylamine, cool to 25 °C, add 40 mL of methanesulfonyl chloride, and keep the reaction at 20-25 °C for 2.5-3.5 h. After the reaction is complete, add 200 mL of water to the reaction solution, adjust the pH to 5-9 with hydrochloric acid, separate the layers, extract the aqueous layer with dichloromethane, combine the organic layers, concentrate the organic layer under reduced pressure to dryness, cool, filter, and dry to obtain 48.4g of compound (3); S3, Esterification reaction: In a clean reaction flask, add 48.4g of compound (3), 180mL of dichloromethane, and 10g of phosphoric acid. Heat to 90-100℃ and keep at 90-100℃ for 4-5 hours. After the reaction is complete, add 10mL of water to terminate the reaction. Concentrate under reduced pressure to dryness, cool, filter, and dry to obtain 47.8g of compound (4). S4. Elimination reaction: In a clean reaction flask, add 47.8g of compound (4), 500 mL of acetone and 30 g of sodium carbonate, heat to 50-60 ℃, and keep the temperature at 50-60 ℃ for 7.5-8.5 h. After the reaction is complete, concentrate under reduced pressure to dryness, add water to precipitate, cool, filter, and dry to obtain 46.3g of compound (5); S5. Oxidation reaction: In a clean reaction flask, add 46.3g of compound (5), 2400 mL of acetone, 20 g of glacial acetic acid, 120 mL of water and 30 g of potassium permanganate. Keep the reaction at 20-25 °C for 1.5-2.5 h. After the reaction is complete, add sodium sulfite aqueous solution to terminate the reaction, filter, concentrate the filtrate under reduced pressure to dryness, cool, filter, and dry to obtain 45.9g of compound (6). S6. Hydrolysis reaction: In a clean reaction flask, add 45.9g of compound (6), 400 mL of acetone, and 200 mL of dichloromethane. Cool to -10 to -5 ℃ and add 13g of potassium carbonate aqueous solution (3g of potassium carbonate dissolved in 10g of water) dropwise. The dropwise addition time is about 0.5 to 1 h. After the dropwise addition is complete, cool to -10 to -5 ℃ and keep the temperature at -10 to -5 ℃ for 2 to 3 h. After the reaction is complete, adjust the pH to 6 to 8 with glacial acetic acid. Concentrate the reaction solution to dryness, cool, filter, and dry to obtain 41.5g of compound (7). S7. Condensation reaction: In a clean reaction flask, add 500 mL of acetonitrile, 500 mL of dichloromethane, 41.5 g of compound (7) and 330 mL of 36.5% hydrochloric acid, stir for 0.5 h, add 30 mL of n-butyraldehyde dropwise at room temperature, and after the addition is complete, keep the reaction at 20-30 ℃ for 2-3 h. After the reaction is complete, add 100 mL of water to terminate the reaction, separate the layers, concentrate the organic phase to dryness under reduced pressure, add 750 mL of ethyl acetate, add 200 mL of water, separate the layers, extract the aqueous layer with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add 25 mL of acetone and 25 mL of isopropyl ether, stir for 2 h, cool to 0-5 ℃, stir for 2 h, continue to cool to -5-0 ℃, stir overnight, filter and dry to obtain 35.6 g of budesonide.

[0044] The yield of budesonide obtained in this example was 71.2%, and the HPLC content was 99.6%.

[0045] Compare with Example 1 This comparative example is basically the same as Example 1, except that in the sulfonation reaction stage, trifluoroacetic acid is used to protect position 11.

[0046] Figure 2 The figures show TLC layer diagrams of the 11-position protectants obtained in Example 1 and Comparative Example 1. As can be seen from the figures, the amount of eliminators obtained by using trifluoroacetic acid as a protectant is significantly greater than that in Example 1.

[0047] Compare with Example 2 This comparative example is basically the same as Example 1, except that: after the condensation reaction, the condensation product was purified by silica gel column chromatography and eluted with ethyl acetate.

[0048] The yield of budesonide obtained in this control example was 60.5%, and the HPLC content was 99.8%.

[0049] Compare with Example 3 This comparative example is basically the same as Example 1, except that: the 17th position of compound (3) is not protected and directly undergoes an elimination reaction to generate compound (5).

[0050] Figure 3 The TLC lattice diagrams of the eliminators obtained in Example 1 and Comparative Example 3 show that the 17th position is not protected. The hydroxyl group at the 17th position of the compound of formula (3) will undergo self-dehydration to form an ether, resulting in incomplete reaction of the raw materials and thus affecting the purification of the final product.

[0051] The yield of budesonide obtained in this control example was 51.6%, and the HPLC content was 85.2%.

[0052] Compare with Example 4 Refer to the method disclosed in WO92 / 11280 for synthesizing budesonide from prednisone as a starting material through cyclization, ring opening, esterification, elimination, oxidation, condensation and hydrolysis reactions.

[0053] The overall yield of this method is only about 20%.

[0054] Compare with Example 5 The method for synthesizing budesonide is based on a method disclosed in Chinese patent CN111560047A, which uses prednisolone acetate as a starting material and proceeds through protection, dehydration, dihydroxylation, hydrolysis, and condensation reactions.

[0055] The yield of this method can reach 61.8%, and the HPLC content can reach 99.3%.

[0056] However, this method has problems such as expensive starting materials, harsh reaction conditions, many by-products, and difficulty in product purification.

[0057] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing budesonide, characterized in that, Includes the following steps: S1. Under alkaline conditions, using the compound of formula (1) as a raw material, an ester group at position 21 is constructed through a substitution reaction to obtain the compound of formula (2). The base used is potassium acetate or sodium acetate. S2. Under alkaline conditions, the compound of formula (2) undergoes a sulfonation reaction, in which the 11-hydroxyl group reacts with a sulfonating agent to form methanesulfonate, yielding the compound of formula (3), wherein the sulfonating agent used is methanesulfonyl chloride; S3. Under acidic conditions, the compound of formula (3) undergoes an esterification reaction, in which the 17-hydroxyl group is condensed with a carboxylic acid / anhydride under acid catalysis to obtain the compound of formula (4). The acid / anhydride used in the esterification reaction includes any one or more combinations of acetic acid, acetic anhydride, concentrated sulfuric acid, phosphoric acid, hydrochloric acid and p-toluenesulfonic acid; the solvent used includes any one or more combinations of toluene, acetic acid and dichloromethane; wherein, the amount of solvent and acid / anhydride required for each 1 g of compound of formula (3) is 1-10 mL and 0.1-3 g, respectively; the temperature is controlled at 60-120 °C and the time is 2-8 h. S4. Under alkaline conditions, compound (4) undergoes an elimination reaction to obtain compound (5). The base used in the elimination reaction includes any one or more combinations of potassium hydroxide, potassium carbonate, potassium acetate, and sodium carbonate. During the elimination reaction, the temperature is controlled at 30–80 °C, the time is 5–15 h, and the solvent used includes any one or more combinations of toluene, acetone, dichloromethane, and N,N-dimethylformamide. The amount of solvent and base required for each 1 g of compound (4) is 7–12 mL and 0.2–2 g, respectively. S5. Under acidic conditions, compound (5) undergoes an oxidation reaction to obtain compound (6); S6. Under alkaline conditions, the compound of formula (6) undergoes a hydrolysis reaction to obtain the compound of formula (7); S7. Under acidic conditions, the compound of formula (7) undergoes a condensation reaction to obtain budesonide of formula (8). After the condensation reaction is completed, a mixed solvent of acetone and isopropyl ether is used to gradually cool and crystallize the product. The reaction process is as follows: 。 2. The synthesis method according to claim 1, characterized in that, In step S1, during the displacement reaction, The solvents used include any one or more combinations of ethyl acetate, toluene, acetone, tetrahydrofuran, dichloromethane, dioxane, and N,N-dimethylformamide. Among them, the amount of solvent and base required for each 1 g of compound (1) is 1-10 mL and 0.1-5 g, respectively; During the displacement reaction, the temperature is controlled at 45–105 °C and the time is controlled at 1–10 h.

3. The synthesis method according to claim 1, characterized in that, In step S2, during the sulfonation reaction, The solvents used include any one or more combinations of acetone, dichloromethane, toluene, and cyclohexane. The bases used include any one or more combinations of sodium methoxide, pyridine, diethylamine, triethylamine, and morpholine. Among them, the amounts of solvent, alkali and sulfonating agent required for each 1 g of compound (2) are 1-10 mL, 0.5-5 mL and 0.3-3 mL, respectively; During the sulfonation reaction, the temperature is controlled at -20 to 30 °C, and the time is controlled at 1 to 10 h.

4. The synthesis method according to claim 1, characterized in that, In step S5, during the oxidation reaction, The solvents used include any one or more combinations of toluene, acetone, and dichloromethane; The acids used include any one or more combinations of formic acid, concentrated sulfuric acid, glacial acetic acid, and phosphoric acid; The oxidizing agents used include any one or more combinations of sodium hypochlorite, potassium permanganate, chromic anhydride, and manganese dioxide. Among them, the required amounts of solvent, acid and oxidant for each 1 g of compound (5) are 20-70 mL, 0.1-1 g and 0.2-2 g, respectively; During the oxidation reaction, the temperature is controlled at 0–50 °C and the time is controlled at 1–5 h.

5. The synthesis method according to claim 1, characterized in that, In step S6, during the hydrolysis reaction, The solvents used include any one or more combinations of toluene, methanol, acetone, and dichloromethane. The alkali used includes any one or more combinations of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium acetate. Among them, the required amounts of solvent and base for each 1 g of compound (6) are 5-15 mL and 0.01-0.1 g, respectively; During the hydrolysis reaction, the temperature is controlled at -30 to 30 ℃ and the time is controlled at 1 to 5 h.

6. The synthesis method according to claim 1, characterized in that, In step S7, during the condensation reaction, The solvents used include any one or more combinations of N,N-dimethylformamide, acetonitrile, acetone, dichloromethane, and chloroform. The acids used include any one or more combinations of hydrochloric acid, p-toluenesulfonic acid, phosphoric acid, and perchloric acid. The condensing agent used is n-butyraldehyde. Among them, the required amounts of solvent, acid and condensing reagent for each 1 g of compound (7) are 10-60 mL, 1-10 mL and 0.2-2 mL, respectively; During the condensation reaction, the temperature is controlled at 0–50 °C and the time is controlled at 2–7 h.

7. The synthesis method according to claim 1, characterized in that, In step S7, after the condensation reaction is completed, water is added to terminate the reaction, the reaction solution is concentrated to dryness, ethyl acetate is added for layer extraction, the obtained extract phase is dried and filtered by anhydrous sodium sulfate, then ethyl acetate is concentrated to dryness, a mixed solvent of acetone and isopropyl ether is added for gradient cooling and crystallization, and after filtration and drying, budesonide of formula (8) is obtained.

8. The synthesis method according to claim 7, characterized in that, During the gradient cooling process, the temperature is first lowered to 0–5 °C and stirred for 1–3 h, then further lowered to -5–0 °C and stirred overnight.

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