A process for the preparation of a budesonide metabolite
The five-step synthetic route for preparing budesonide metabolites solves the problem of the lack of synthetic methods in the existing technology, realizes the production of high-purity budesonide metabolites, and is suitable for industrial application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- TLC NANJING PHARMA RANDD CO LTD
- Filing Date
- 2023-12-25
- Publication Date
- 2026-07-03
AI Technical Summary
Currently, there are no reported methods for synthesizing budesonide metabolites, which affects comprehensive analysis and research on their clinical, pharmacological, pharmacokinetic, and toxicological aspects.
A five-step synthetic route was adopted, including the reaction of compound I with perchloric acid and crotonaldehyde to generate intermediate II, the reaction of intermediate II with acetic anhydride to generate III, the reaction of III with dibromohydantoin and perchloric acid to generate IV, the reaction of IV with azobisisobutyronitrile and tri-n-butyltin hydride to generate V, and finally the reaction with an inorganic base to generate budesonide metabolite VI.
The high-purity synthesis of budesonide metabolites, with a purity of over 96%, has been achieved. The process is highly operable and suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention pertains to compound synthesis methods, specifically relating to a method for preparing budesonide metabolites. Background Technology
[0002] Budesonide, chemically named 16alpha,17alpha-22R,S-propylmethylenedioxy-pregn-1,4-diene-11beta,21-dihydroxy-3,20-dione, with a molecular weight of 430.54, is a glucocorticoid with highly potent local anti-inflammatory effects. It enhances the stability of endothelial cells, smooth muscle cells, and lysosomal membranes, inhibits immune responses, and reduces antibody synthesis, thereby decreasing the release and activity of histamine and other allergic mediators. It also alleviates the enzymatic processes triggered by antigen-antibody binding and inhibits the synthesis and release of bronchoconstrictive substances, thus reducing smooth muscle contraction. Clinically, it is used for patients with glucocorticoid-dependent or non-dependent bronchial asthma and asthmatic chronic bronchitis.
[0003] Pharmacokinetics plays an increasingly important role in drug development, shortening the development cycle, reducing costs, and providing a new pathway for drug discovery. Budesonide metabolite (compound VI) has a molecular weight of 446.55 and the molecular formula is C0.05. 25 H 34 O7, chemically named (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-10-(1-hydroxypropyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]inde no[1,2-d][1,3]dioxol-4-one, has the following structural formula. Drug Metabolism and Disposition (1987), 15(3), 403-11, reported it as a metabolite of budesonide. Currently, no synthetic methods for budesonide metabolites have been reported. In order to conduct a comprehensive analysis and study of the clinical, pharmacological, pharmacokinetic, and toxicological aspects of budesonide, it is necessary to design and develop a method for preparing budesonide metabolites, so as to provide a reference substance for the comprehensive analysis of the clinical, pharmacological, pharmacokinetic, and toxicological aspects of budesonide.
[0004] Summary of the Invention
[0005] Purpose of the invention: The purpose of this invention is to provide a method for preparing budesonide metabolites.
[0006] Technical solution: The method for preparing budesonide metabolites according to the present invention includes the following steps:
[0007] (1) Compound I was suspended in dioxane, and perchloric acid and crotonaldehyde were added. The mixture was stirred to obtain intermediate product II:
[0008]
[0009] (2) Take intermediate product II, dissolve it in pyridine, add acetic anhydride in an ice bath, and stir the reaction to obtain intermediate product III:
[0010]
[0011] (3) Dissolve intermediate product III in acetonitrile, add perchloric acid and dibromohydantoin, and react to obtain intermediate product IV:
[0012]
[0013] (4) Dissolve intermediate IV in acetonitrile, add azobisisobutyronitrile and tri-n-butyltin hydride, and react to obtain intermediate V:
[0014]
[0015] (5) Dissolve intermediate product V in methanol, add an inorganic base and react to obtain target product VI:
[0016]
[0017] Preferably, in step (1), the molar ratio of compound I to perchloric acid and crotonaldehyde is 1:3 to 10:3 to 6; the reaction is carried out at room temperature for 1 to 10 hours.
[0018] More preferably, in step (1), the molar ratio of compound I to perchloric acid and crotonaldehyde is 1:3:3; the reaction is carried out at room temperature for 2 hours.
[0019] Preferably, in step (1), the raw materials are reacted completely, slowly poured into water under ice bath, the pH is adjusted to alkaline with an inorganic base, extracted with ethyl acetate, the organic layers are combined and dried with anhydrous sodium sulfate, filtered, and evaporated to obtain intermediate product II.
[0020] Preferably, in step (2), the molar ratio of intermediate product II to acetic anhydride is 1:5 to 10; the reaction temperature is 20 to 30°C, and the reaction time is 5 to 10 hours.
[0021] More preferably, in step (2), the molar ratio of intermediate product II to acetic anhydride is 1:2 to 3; the reaction is carried out by stirring at room temperature for 5-6 hours.
[0022] Preferably, in step (3), the molar ratio of intermediate product III to dibromohydantoin is 1:2 to 10.
[0023] More preferably, the molar ratio of intermediate product III to dibromohydantoin in step (3) is 1:2 to 4.
[0024] Preferably, in step (3), the molar ratio of intermediate product III to perchloric acid is 1:2 to 10.
[0025] Preferably, the reaction temperature in step (3) is 20-30°C and the reaction time is 4-10 hours.
[0026] More preferably, the reaction in step (3) is carried out with stirring at room temperature for 4 to 6 hours.
[0027] Preferably, in step (4), the molar ratio of intermediate product IV to azobisisobutyronitrile and tri-n-butyltin hydride is 1:0.1 to 1:1 to 10; the reaction temperature is 80 to 100°C and the reaction time is 6 to 10 hours.
[0028] More preferably, in step (4), the molar ratio of intermediate product IV to azobisisobutyronitrile and tri-n-butyltin hydride is 1:0.1-0.3:1-3; the reaction temperature is 100°C and the reaction time is 6-8 hours.
[0029] Preferably, in step (5), the molar ratio of intermediate product V to inorganic base is 1:4 to 10; the reaction temperature is 20 to 30°C, and the reaction time is 5 to 8 hours.
[0030] More preferably, in step (5), the molar ratio of intermediate product V to inorganic base is 1:4 to 6; the reaction is carried out by stirring at room temperature for 5-6 hours.
[0031] Preferably, the inorganic base in step (5) is any one of sodium carbonate, potassium carbonate, and cesium carbonate.
[0032] More preferably, the inorganic base in step (5) is potassium carbonate.
[0033] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the preparation method of the present invention is highly operable, the process design is reasonable, and industrial production can be realized. Moreover, the reagents used in the synthesis method are simple and readily available. The budesonide metabolites prepared have a purity of over 96%. Attached Figure Description
[0034] Figure 1 The mass spectrum of compound II prepared in Example 1 of this invention;
[0035] Figure 2 The NMR spectrum of compound II prepared in Example 1 of this invention;
[0036] Figure 3 The NMR spectrum of compound III prepared in Example 1 of this invention;
[0037] Figure 4 The mass spectrum of compound IV prepared in Example 1 of this invention;
[0038] Figure 5 The NMR spectrum of compound IV prepared in Example 1 of this invention;
[0039] Figure 6 The mass spectrum of compound V prepared in Example 1 of this invention;
[0040] Figure 7 The NMR spectrum of compound V prepared in Example 1 of this invention;
[0041] Figure 8 The mass spectrum of compound VI prepared in Example 1 of this invention;
[0042] Figure 9 The NMR spectrum is that of compound VI prepared in Example 1 of this invention. Detailed Implementation
[0043] The technical solution of the present invention will be further described below with reference to the accompanying drawings.
[0044] The method for preparing the budesonide metabolite of the present invention is as follows:
[0045]
[0046] Example 1
[0047] Preparation of Compound II: 30 g of 16alpha-hydroxyprednisolone and 20 g of crotonaldehyde were suspended in 0.6 L of dioxane. 20 g of perchloric acid was added, and the mixture was stirred at room temperature for 1 hour. No reactants remained. The reaction solution was adjusted to pH 7-8 with potassium carbonate, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The resulting crude product was evaporated to dryness to obtain 38 g. Column chromatography was used to separate 34 g of intermediate II, with a yield of 99%. Mass spectra are shown below. Figure 1 See MRI Figure 2 .
[0048] Preparation of Compound III: 34 g of intermediate II was dissolved in 0.5 L of pyridine, and 16 g of acetic anhydride was added. The mixture was stirred overnight at room temperature. No raw material remained. The solution was directly evaporated to dryness, and purified by column chromatography to obtain 30 g of intermediate III, with a yield of 81%. NMR results are shown below. Figure 3 .
[0049] Preparation of compound IV: 30 g of compound III was suspended in 0.3 L of acetonitrile, and 1.6 g of perchloric acid and 5 g of dibromohydantoin were added. The mixture was stirred at room temperature for 2 hours. No raw material remained. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography purification yielded 23 g of compound IV, with a yield of 75%. Mass spectrometry is shown below. Figure 4 See MRI Figure 5 .
[0050] Preparation of compound V: 23 g of compound IV, 1 g of azobisisobutyronitrile, and 36 ml of tri-n-butyltin hydride were dissolved in 0.24 L of dry THF. The mixture was refluxed and stirred for 3 hours. No starting material remained. The solution was purified by rotary cyclohexane column chromatography to obtain 12 g of intermediate V, with a yield of 65%. Mass spectrometry is shown below. Figure 6 See MRI Figure 7 .
[0051] Preparation of compound VI: 12 g of compound V was dissolved in methanol, and 5.7 g of potassium carbonate was added. The mixture was stirred at room temperature for 3 hours until no starting material remained. The mixture was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. The dried phase was then purified by column chromatography to obtain 4.5 g of the final product VI, with a yield of 50%. Mass spectrometry is shown below. Figure 8 See MRI Figure 9 .
[0052] Example 2
[0053] Preparation of compound II: 40 g of 16alpha-hydroxyprednisolone and 30 g of crotonaldehyde were suspended in 0.8 L of dioxane, 30 g of perchloric acid was added, and the mixture was stirred at room temperature for 1 hour. No raw material remained. The pH of the reaction solution was adjusted to 7-8 with potassium carbonate, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and separated by column chromatography to obtain 39 g of intermediate product II, with a yield of 86%.
[0054] Preparation of compound III: 39 g of intermediate II was dissolved in 0.6 L of pyridine, 20 g of acetic anhydride was added, and the mixture was stirred overnight at room temperature. No raw material remained. The mixture was directly evaporated to dryness and purified by column chromatography to obtain 28 g of intermediate III, with a yield of 65%.
[0055] Preparation of compound IV: 28g of compound III was suspended in 0.28L of acetonitrile, 0.9g of perchloric acid and 6g of dibromohydantoin were added, and the mixture was stirred at room temperature for 2 hours. No raw material was left. The mixture was extracted with dichloromethane, and the organic phases were combined and dried with anhydrous sodium sulfate. The mixture was then evaporated to dryness and purified by column chromatography to obtain 20g of compound IV, with a yield of 59%.
[0056] Preparation of compound V: 20g of compound IV, 1.5g of azobisisobutyronitrile and 30ml of tri-n-butyltin hydride were dissolved in 0.20L of dry THF, refluxed and stirred for 3 hours. No raw material was left. The product was purified by rotary evaporation and column chromatography to obtain 8g of intermediate product V, with a yield of 46%.
[0057] Preparation of final product VI: 8g of compound V was dissolved in methanol, 5.0g of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. No raw material was left. The mixture was extracted with dichloromethane, and the organic phases were dried with anhydrous sodium sulfate. The mixture was then evaporated to dryness and purified by column chromatography to obtain 2.5g of final product VI, with a yield of 34%.
[0058] Example 3
[0059] Preparation of compound II: 50 g of 16alpha-hydroxyprednisolone and 40 g of crotonaldehyde were suspended in 1.0 L of dioxane, 40 g of perchloric acid was added, and the mixture was stirred at room temperature for 1 hour. No raw material remained. The pH of the reaction solution was adjusted to 7-8 with potassium carbonate, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and separated by column chromatography to obtain 40 g of intermediate product II, with a yield of 70%.
[0060] Preparation of compound III: 40 g of intermediate II was dissolved in 0.6 L of pyridine, and 25 g of acetic anhydride was added. The mixture was stirred overnight at room temperature. With no raw material remaining, the solution was directly evaporated to dryness and purified by column chromatography to obtain 31 g of intermediate III, with a yield of 71%.
[0061] Preparation of compound IV: 31g of compound III was suspended in 0.31L of acetonitrile, 1.0g of perchloric acid and 7g of dibromohydantoin were added, and the mixture was stirred at room temperature for 2 hours. No raw material was left. The mixture was extracted with dichloromethane, and the organic phases were combined and dried with anhydrous sodium sulfate. The mixture was then evaporated to dryness and purified by column chromatography to obtain 20g of compound IV, with a yield of 53%.
[0062] Preparation of compound V: 20g of compound IV, 3g of azobisisobutyronitrile and 25ml of tri-n-butyltin hydride were dissolved in 0.30L of dry THF, refluxed and stirred for 3 hours. No raw material was left. The intermediate product V was purified by rotary column chromatography with a yield of 58%.
[0063] Preparation of final product VI: 10g of compound V was dissolved in methanol, 7.0g of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. No raw material was left. The mixture was extracted with dichloromethane, and the organic phases were combined and dried with anhydrous sodium sulfate. The mixture was then evaporated to dryness and purified by column chromatography to obtain 3g of final product VI, with a yield of 32%.
Claims
1. A method for preparing budesonide metabolites, characterized in that, Includes the following steps: (1) Compound I was suspended in dioxane, and perchloric acid and crotonaldehyde were added. The mixture was stirred to obtain intermediate product II: (2) Take intermediate product II, dissolve it in pyridine, add acetic anhydride in an ice bath, and stir the reaction to obtain intermediate product III: (3) Dissolve intermediate product III in acetonitrile, add perchloric acid and dibromohydantoin, and react to obtain intermediate product IV: (4) Dissolve intermediate IV in acetonitrile, add azobisisobutyronitrile and tri-n-butyltin hydride, and react to obtain intermediate V: (5) Dissolve intermediate product V in methanol, add an inorganic base and react to obtain target product VI:
2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound I to perchloric acid and crotonaldehyde is 1:3 to 10:3 to 6; the reaction is carried out at room temperature for 1 to 10 hours.
3. The preparation method according to claim 1, characterized in that, In step (1), the raw materials react completely, are slowly poured into water under an ice bath, the pH is adjusted to alkaline with an inorganic base, extracted with ethyl acetate, the organic layers are combined and dried with anhydrous sodium sulfate, filtered, and evaporated to obtain intermediate product II.
4. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of intermediate product II to acetic anhydride is 1:5 to 10; the reaction temperature is 20 to 30°C, and the reaction time is 5 to 10 hours.
5. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of intermediate product III to dibromohydantoin is 1:2 to 10.
6. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of intermediate product III to perchloric acid is 1:2 to 10.
7. The preparation method according to claim 1, characterized in that, The reaction temperature in step (3) is 20-30°C and the reaction time is 4-10 hours.
8. The preparation method according to claim 1, characterized in that, In step (4), the molar ratio of intermediate product IV to azobisisobutyronitrile and tri-n-butyltin hydride is 1:0.1 to 1:1 to 10; the reaction temperature is 80 to 100°C and the reaction time is 6 to 10 hours.
9. The preparation method according to claim 1, characterized in that, In step (5), the molar ratio of intermediate product V to inorganic base is 1:4 to 10; the reaction temperature is 20 to 30°C, and the reaction time is 5 to 8 hours.
10. The preparation method according to claim 1, characterized in that, In step (5), the inorganic base is any one of sodium carbonate, potassium carbonate, or cesium carbonate.