Preparation method of budesonide
By performing specific reaction and treatment steps in dioxane, high-quality budesonide is prepared, which solves the safety and environmental protection problems of the extraction process in the prior art, and realizes a high-efficiency and low-energy consumption preparation process.
Patent Information
- Application Number
- CN202411386491.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-29
- Publication Date
- 2025-02-18
AI Technical Summary
In the existing budesonide preparation method, the extraction process can easily cause the extraction solvent to evaporate, causing human body damage and environmental pollution. The extractors dichloromethane and trichloromethane used at the same time are strictly controlled, which increases production costs and environmental risks.
A new preparation method is adopted to react 16α-hydroxyprednisolone with n-butyraldehyde in dioxane, and add perchloric acid mixture dropwise under stirring to control the reaction temperature between 10-35 °C, then neutralize to a pH of 5-10, cure and filtration, and finally purify it with an organic solvent to obtain the finished budesonide product.
The method is easy to obtain raw materials, short process route, easy operation, high yield, mild reaction, low energy consumption, high quality of finished products, comply with the requirements of European and American pharmacopoeia, and avoids the use of harmful extractants, reducing production costs and environmental risks .
Smart Images
Figure CN119462815A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of budesonide, an asthma drug. Background Art
[0002] Budesonide is a glucocorticoid drug with strong anti-inflammatory effects and can be used to treat asthma. Its structural formula is:
[0003]
[0004] At present, the conventional preparation route is as follows:
[0005]
[0006] In the existing patented synthesis process, after budesonide is prepared by condensation reaction, it is usually separated from the reaction solution by extraction. However, the extraction solvent is easily volatilized during the extraction process, causing human harm and environmental pollution.
[0007] The commonly used extraction agents dichloromethane and chloroform are included in the "National List of New Pollutants under Key Control" (2023 edition), and key controls are implemented in many aspects such as production, use and emissions, which greatly increases the production cost and environmental risks of budesonide raw materials.
[0008] In summary, the development of new, rapid, convenient and efficient new technologies for the preparation of budesonide with industrial prospects has significant social and economic benefits. Summary of the invention
[0009] The technical problem to be solved by the present invention is to overcome the defects of the prior art and provide a preparation method of budesonide.
[0010] In order to solve the above technical problems, the present invention provides the following technical solutions:
[0011] The preparation method of the present invention mainly comprises the following steps:
[0012] (1) Add 16α-hydroxyprednisolone and n-butyraldehyde to dioxane, stir evenly, and adjust the liquid temperature to 10-35° C.;
[0013] (2) Mix perchloric acid and dioxane evenly, and adjust the liquid temperature to 10-35° C.;
[0014] (3) under stirring, the mixed solution of step (2) is added dropwise to the mixed solution of step (1), and the mixture is stirred for reaction for 4-10 hours after the addition is completed;
[0015] (4) adding an alkaline solution to neutralize the reaction solution to a pH of 5-10;
[0016] (5) adding the neutralized liquid into water under stirring to solidify for 0.5-10 hours;
[0017] (6) filtering the solidified material to obtain a crude budesonide product, and refining the crude budesonide product with an organic solvent to obtain a finished budesonide product.
[0018] Furthermore, in step (1), the weight ratio of 16α-hydroxyprednisolone to dioxane is 1:2-10; wherein the molar ratio of 16α-hydroxyprednisolone to n-butyraldehyde is 1:1-4.
[0019] Furthermore, the weight ratio of perchloric acid to dioxane in step (2) is 1:2-10; wherein the molar ratio of perchloric acid to 16α-hydroxyprednisolone in step (1) is 0.1-0.5:1.
[0020] Furthermore, the reaction temperature in step (3) is 10-35°C, preferably 15-25°C.
[0021] Furthermore, the solute of the alkaline solution in step (4) is one or more of potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate; wherein the mass fraction of the alkaline solution is 5-20%.
[0022] Furthermore, the curing reaction temperature in step (5) is 0-35°C, preferably 5-15°C; wherein the amount of water used is 3-20 times the amount of dioxane used in step (1); wherein the curing method is stirring curing or standing curing after stirring and adding.
[0023] Furthermore, the organic solvent in step (6) is one or more of methanol, ethanol, acetone or dioxane; wherein the crude budesonide product is purified by dissolving, concentrating, crystallizing, filtering and drying the obtained solid material once or multiple times with one or more organic solvents.
[0024] Compared with the prior art, the present invention has the following beneficial effects:
[0025] 1. The raw materials of the present invention are easily available, the process route is short, the operation is simple and convenient, and the yield is high.
[0026] 2. The present invention has mild reaction, low energy consumption and low requirements on reaction equipment.
[0027] 3. The finished product of the present invention has high quality and can meet the requirements of European and American pharmacopoeias.
[0028] 4. The present invention avoids the use of dichloromethane or chloroform as an extractant, thereby reducing production costs and environmental risks. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:
[0030] Figure 1 It is a reaction schematic diagram of the present invention; DETAILED DESCRIPTION
[0031] The preferred embodiments of the present invention are described below in conjunction with the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.
[0032] Example 1
[0033] 20.00g 16α-hydroxyprednisolone, 18.00g n-butyraldehyde and 160.00g dioxane were added to the reaction bottle, stirred evenly, and the temperature of the liquid was adjusted to 15°C. 3.50g perchloric acid and 20.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 15°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 10-20°C for 7 hours, and 12.00g 18% sodium bicarbonate solution was added. Under stirring, the reaction solution was added to 2.00kg 15°C water. After the addition was completed, the mixture was stirred and solidified at 15-20°C for 2 hours. The solidified material was filtered and dried to obtain 22.40g of crude budesonide, with a yield of 112.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 92.6%.
[0034] The crude budesonide was refined with 270 g of ethanol, 320 g of acetone and 170 g of ethanol in sequence to obtain 14.56 g of budesonide finished product with a yield of 72.8% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 99.8%, the proportion of diastereomer A was 45.6%, the content of unknown single impurity was 0.07%, the content of impurity A was 0.13%, the content of impurity D was 0.10%, and the content of impurity L was 0.12%.
[0035] Example 2
[0036] 20.00g 16α-hydroxyprednisolone, 18.00g n-butyraldehyde and 180.00g dioxane were added to the reaction bottle, stirred evenly, and the temperature of the feed liquid was adjusted to 25°C. 3.00g perchloric acid and 30.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 25°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 25-30°C for 5 hours, and 14.00g 16% potassium bicarbonate solution was added. Under stirring, the reaction solution was added to 3.00kg 20°C water. After the addition was completed, the mixture was stirred and solidified at 18-25°C for 3 hours. The solidified material was filtered and dried to obtain 22.00g of crude budesonide, with a yield of 110.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 92.8%.
[0037] The crude budesonide was refined with 260 g of methanol, 320 g of acetone and 160 g of methanol in sequence to obtain 14.96 g of budesonide finished product with a yield of 74.8% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 99.6%, the proportion of diastereomer A was 46.3%, the content of unknown single impurity was 0.06%, the content of impurity A was 0.15%, the content of impurity D was 0.12%, and the content of impurity L was 0.09%.
[0038] Example 3
[0039] 20.00g 16α-hydroxyprednisolone, 10.00g n-butyraldehyde and 130.00g dioxane were added to the reaction bottle, stirred evenly, and the temperature of the liquid was adjusted to 30°C. 2.70g perchloric acid and 20.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 30°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 28-34°C for 4 hours, and 10.00g 12% sodium carbonate solution was added. Under stirring, the reaction solution was added to 1.30kg 25°C water. After the addition was completed, the mixture was stirred and solidified at 23-28°C for 2 hours. The solidified material was filtered and dried to obtain 23.00g of crude budesonide, with a yield of 115.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 92.5%.
[0040] The crude budesonide was refined with 280 g of methanol, 190 g of dioxane and 180 g of methanol in sequence to obtain 14.72 g of budesonide finished product with a yield of 73.6% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 99.7%, the proportion of diastereomer A was 46.8%, the content of unknown single impurity was 0.08%, the content of impurity A was 0.12%, the content of impurity D was 0.14%, and the content of impurity L was 0.10%.
[0041] Example 4
[0042] 20.00g 16α-hydroxyprednisolone, 8.00g n-butyraldehyde and 90.00g dioxane were added to the reaction bottle, stirred evenly, and the temperature of the liquid was adjusted to 30°C. 2.00g perchloric acid and 10.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 30°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 25-30°C for 6 hours, and 11.00g 10% potassium carbonate solution was added. Under stirring, the reaction solution was added to 1.00kg 25°C water. After the addition was completed, it was allowed to stand and solidify for 8 hours at 24-30°C. The solidified material was filtered and dried to obtain 21.60g of crude budesonide, with a yield of 108.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 93.4%.
[0043] The crude budesonide was refined with 260 g of ethanol, 170 g of dioxane and 160 g of ethanol in sequence to obtain 14.26 g of budesonide finished product with a yield of 71.28% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 99.7%, the proportion of diastereomer A was 46.4%, the content of unknown single impurity was 0.07%, the content of impurity A was 0.13%, the content of impurity D was 0.10%, and the content of impurity L was 0.10%.
[0044] Example 5
[0045] 100.00g 16α-hydroxyprednisolone, 40.00g n-butyraldehyde and 500.00g dioxane were added to the reaction bottle, stirred evenly, and the temperature of the liquid was adjusted to 20°C. 12.00g perchloric acid and 60.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 20°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 20-26°C for 6 hours, and 60.00g 12% potassium carbonate solution was added. Under stirring, the reaction solution was added to 4.00kg 20°C water. After the addition was completed, it was allowed to stand and solidify for 9 hours at 20-26°C. The solidified material was filtered and dried to obtain 114.00g of crude budesonide, with a yield of 114.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 93.0%.
[0046] The crude budesonide was refined with 1.20 kg ethanol, 700 g dioxane, 900 g ethanol and 800.00 g ethanol in sequence to obtain 66.12 g of budesonide finished product with a yield of 66.0% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 100.2%, the proportion of diastereomer A was 43.6%, the content of unknown single impurity was 0 (less than 0.05% was not included), the content of impurity A was 0.08%, the content of impurity D was 0.06%, and the content of impurity L was 0.10%.
[0047] Example 6
[0048] 100.00g 16α-hydroxyprednisolone, 50.00g n-butyraldehyde and 600.00g dioxane were added to the reaction bottle, stirred evenly, and the temperature of the liquid was adjusted to 25°C. 12.00g perchloric acid and 60.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 25°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 24-30°C for 7 hours, and 45.00g 15% sodium bicarbonate solution was added. Under stirring, the reaction solution was added to 4.20kg 25°C water. After the addition was completed, the mixture was stirred and solidified at 24-28°C for 2 hours. The solidified material was filtered and dried to obtain 115.00g of crude budesonide, with a yield of 115.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 93.1%.
[0049] The crude budesonide was refined with 1.30 kg methanol, 1.60 g acetone, 900 g dioxane and 800.00 g methanol in sequence to obtain 71.30 g of budesonide finished product with a yield of 71.0% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 100.8%, the proportion of diastereomer A was 43.7%, the content of unknown single impurity was 0 (less than 0.05% was not included), the content of impurity A was 0.06%, the content of impurity D was 0 (less than 0.05% was not included), and the content of impurity L was 0.09%.
[0050] Example 7
[0051] 700.00g 16α-hydroxyprednisolone, 300.00g n-butyraldehyde and 2.10kg dioxane were added to the reaction bottle, stirred evenly, and the temperature of the liquid was adjusted to 25°C. 90.00g perchloric acid and 400.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 26°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 25-32°C for 6 hours, and 600.00g 10% sodium bicarbonate solution was added. Under stirring, the reaction solution was added to 30.00kg 15°C water. After the addition was completed, it was stirred and solidified at 14-20°C for 1 hour. The solidified material was filtered and dried to obtain 812.00g of crude budesonide, with a yield of 116.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 93.4%.
[0052] The crude budesonide was refined with 9.80 kg of methanol, 12.00 kg of acetone, 11.00 kg of acetone and 5.80 kg of methanol in sequence to obtain 511.56 g of budesonide finished product with a yield of 73.0% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 100.6%, the proportion of diastereomer A was 42.8%, the content of unknown single impurity was 0 (less than 0.05% was not included), the content of impurity A was 0.10%, the content of impurity D was 0.05%, and the content of impurity L was 0.10%.
[0053] Example 8
[0054] 700.00g 16α-hydroxyprednisolone, 240.00g n-butyraldehyde and 2.80kg dioxane were added to the reaction bottle, stirred evenly, and the temperature of the feed liquid was adjusted to 20°C. 70.00g perchloric acid and 300.00g dioxane were mixed evenly in a beaker and the temperature was adjusted to 20°C. Under stirring, the mixed solution in the beaker was added dropwise to the reaction bottle. After the addition was completed, the reaction was continued to be stirred at 20-30°C for 6 hours, and 350.00g 12% sodium bicarbonate solution was added. Under stirring, the reaction solution was added to 35.00kg 15°C water. After the addition was completed, it was allowed to stand and solidify for 8 hours at 14-20°C. The solidified material was filtered and dried to obtain 798.00g of crude budesonide, with a yield of 114.0% (based on 16α-hydroxyprednisolone) and an HPLC purity of 93.2%.
[0055] The crude budesonide was refined with 9.60 kg of ethanol, 12.00 kg of acetone, 6.00 kg of dioxane and 5.50 kg of ethanol in sequence to obtain 478.80 g of budesonide finished product with a yield of 68.0% (based on 16α-hydroxyprednisolone). HPLC detection was performed according to the detection method of the European Pharmacopoeia. The content of budesonide was 100.9%, the proportion of diastereomer A was 43.7%, the content of unknown single impurity was 0 (less than 0.05% was not included), the content of impurity A was 0.07%, the content of impurity D was 0 (less than 0.05% was not included), and the content of impurity L was 0.08%.
[0056] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for preparing budesonide, characterized in that The following steps are involved: (1) Add 16α-hydroxyprednisolone and n-butyraldehyde to dioxane, stir evenly, and adjust the liquid temperature to 10-35° C.; (2) Mix perchloric acid and dioxane evenly, and adjust the liquid temperature to 10-35° C.; (3) under stirring, the mixed solution of step (2) is added dropwise to the mixed solution of step (1), and the mixture is stirred for reaction for 4-10 hours after the addition is completed; (4) adding an alkaline solution to neutralize the reaction solution to a pH value of 5-10, wherein the solute of the alkaline solution is one or more of potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate; (5) adding the neutralized liquid into water under stirring to solidify for 0.5-10 hours; (6) filtering the solidified material to obtain a crude budesonide product, and refining the crude budesonide product with an organic solvent to obtain a finished budesonide product, wherein the organic solvent is one or more of methanol, ethanol, acetone or dioxane.
2. The preparation method according to claim 1, characterized in that The molar ratio of 16α-hydroxyprednisolone, n-butyraldehyde and perchloric acid is 1:1-4:0.1-0.
5.
3. The preparation method according to claim 1, characterized in that: The weight ratio of the organic solvent in step (1) to the solidification water in step (5) is 1:3-20.
4. The preparation method according to claim 1, characterized in that: In step (1), the weight ratio of 16α-hydroxyprednisolone to dioxane is 1:2-10.
5. The preparation method according to claim 1, characterized in that: In step (2), the weight ratio of perchloric acid to dioxane is 1:2-10.
6. The preparation method according to claim 1, characterized in that: The reaction temperature in step (3) is 10-35°C.
7. The preparation method according to claim 1, characterized in that: The mass fraction of the alkaline solution in step (4) is 5-20%.
8. The preparation method according to claim 1, characterized in that: The curing temperature in step (5) is 0-35°C.
9. The preparation method according to claim 1, characterized in that: The curing method in step (5) is stirring curing or standing curing after stirring and adding.
10. The preparation method according to claim 1, characterized in that: The method for refining the crude budesonide in step (6) is to use one or more organic solvents to dissolve, concentrate, crystallize, filter and dry the obtained solid material once or multiple times.