A processing method for budesonide mother solution
By using acidic conditions of chloroalkane and inorganic acid in budesonide mother liquor and combined with isopropyl ether crystallization system, isomer A was successfully converted into isomer B, solving the problem that the proportion of isomer A in budesonide mother liquor exceeds the range of pharmacopoeia and is difficult to remove impurities, and achieving high purity and high recovery budesonide refined products.
Patent Information
- Application Number
- CN202510062500.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-15
- Publication Date
- 2025-04-01
AI Technical Summary
The prior art is difficult to effectively control the ratio of epimer A in budesonide mother liquor, causing it to exceed the range of the pharmacopoeia, and the impurities L and impurities D generated during the purification of alcohol solvents are difficult to remove, resulting in low product purity and low recovery.
The chloroalkane organic solvent and inorganic acid solution were used for treatment under acidic conditions. Isomer A was converted into isomer B by stirring and standing, and purified by crystallization system of chloroalkane and isopropyl ether. Finally, high-purity budesonide refined products were obtained by heating and filtration of alcohol solvents.
The efficient treatment of budesonide mother liquor is achieved, with high product purity, few impurities, and high recovery efficiency. The HPLC content reaches more than 99.0%, the isomer A ratio is between 40-51%, the impurity content is less than 0.10%, and the yield is more than 80%.
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Figure CN119735628A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical chemistry, in particular to a method for treating a budesonide mother solution. Background Art
[0002] Budesonide is a glucocorticoid with high local anti-inflammatory effect. It can enhance the stability of endothelial cells, smooth muscle cells and lysosomal membranes, inhibit immune response and reduce antibody synthesis, thereby reducing the release and activity of allergic active mediators such as histamine, and can reduce the enzymatic process stimulated by antigen-antibody binding, inhibit the synthesis and release of bronchial contraction substances and reduce the contraction reaction of smooth muscle, and can inhibit early bronchospasm and late allergic reaction. It is one of the important drugs for the treatment of allergic asthma. It has high local anti-inflammatory effect among similar drugs, and its efficacy is significantly stronger than other glucocorticoids. Chemical name: 16a, 17a-22R, S-propylmethylenedioxy-pregnane-1,4-diene-11b, 21-dihydroxy-3,20-dione, CAS: 51333-22-3.
[0003] The structural formula of budesonide:
[0004]
[0005] There are diastereomers A and B in budesonide, and the EP pharmacopoeia stipulates that the proportion of diastereomer A is 40.0% to 51.0%. Currently, it is reported that a variety of refining systems can control diastereomer A in budesonide within the pharmacopoeia range. The commonly used solvents in these methods are alcohol solvents, which result in diastereomer A in the budesonide mother liquor exceeding 60%. After direct refining treatment, the recovery rate is only about 60%. Isomer A is also an effective component of budesonide, and it is directly refined and removed, resulting in waste; in addition, the budesonide mother liquor contains impurities L and impurity D pharmacopoeia specific impurities, and the level in the mother liquor is 0.1-0.2%. These two impurities are side reactions generated during the refining process of alcohol solvents. Refining them with alcohol solvents is still ineffective, resulting in a high impurity content.
[0006] In view of this, the present invention is proposed. Summary of the invention
[0007] The object of the present invention is to provide a method for treating budesonide mother liquor, which can partially convert isomer A into isomer B, has high product purity, few impurities and high recovery efficiency.
[0008] The first aspect of the present invention provides a method for treating a budesonide mother solution, comprising the following steps:
[0009] S1, adding budesonide mother liquor to chloroalkane organic solvent and inorganic acid solution, stirring and standing to separate, washing the organic layer with water and sodium bicarbonate until neutral, concentrating the organic solvent, then adding isopropyl ether dropwise, cooling and crystallizing, filtering, and obtaining a primary refined product;
[0010] S2. adding the primary refined product into an alcohol solvent to heat and dissolve, filtering after dissolving, concentrating the filtrate under reduced pressure, cooling and crystallizing, filtering, and obtaining a refined budesonide product.
[0011] Preferably, in step S1, the chloroalkane organic solvent includes: one or more of dichloromethane and chloroform.
[0012] Preferably, in step S1, the inorganic acid solution comprises: one or more of hydrochloric acid and perchloric acid.
[0013] Preferably, in step S1, the sodium bicarbonate is a 5% sodium bicarbonate solution.
[0014] Preferably, in step S1, the stirring time is 3-6 hours, more preferably 4-5 hours.
[0015] Preferably, in step S1, the feeding ratio of the budesonide mother liquor, the chloroalkane organic solvent, the inorganic acid, the sodium bicarbonate and the isopropyl ether is 1:(5-10):(2.0-6.0):(0.1-0.5):(2-5), wherein the budesonide mother liquor and the sodium bicarbonate are measured in g, and the chloroalkane organic solvent, the inorganic acid and the isopropyl ether are measured in mL.
[0016] Preferably, step S1 comprises: cooling the chloroalkane organic solvent and the inorganic acid solution to -2 to 0°C, adding budesonide mother liquor to the solution, stirring for 3-6 hours, adding water and stirring, standing for stratification, washing the organic layer once with water, stratifying, washing once with sodium bicarbonate solution, stratifying, concentrating the organic solvent, concentrating to half the volume, adding isopropyl ether dropwise, continuing to concentrate, stirring and cooling to 0-5°C for crystallization, and filtering to obtain a primary refined product.
[0017] Preferably, in step S2, the feed ratio of the primary refined product to the alcohol solvent is 1:(10.0-15.0), wherein the primary refined product is measured in g and the alcohol solvent is measured in mL.
[0018] Preferably, in step S2, the alcohol solvent is methanol.
[0019] Preferably, step S2 comprises: adding the primary refined product into methanol to heat and dissolve, filtering after dissolving, concentrating the filtrate under reduced pressure, cooling to 0-5° C. for crystallization, filtering, and obtaining a refined budesonide product.
[0020] The second aspect of the present invention provides a refined budesonide product, which is prepared by the above-mentioned method for treating the budesonide mother liquor.
[0021] The present invention has at least the following beneficial effects:
[0022] (1) The treatment method of the present invention effectively converts diastereomer A into diastereomer B under acidic conditions, and processes the budesonide mother liquor into a qualified budesonide refined product through a chloroalkane organic solvent and isopropyl ether crystallization system.
[0023] (2) The product obtained by the treatment method of the present invention has high purity, few impurities and high recovery efficiency. Its HPLC content reaches more than 99.0%, any impurity is less than 0.10%, isomer A is 40-51%, and the yield is more than 80%.
[0024] (3) The treatment method of the present invention is simple to operate, energy-saving and consumption-reducing, green and environmentally friendly, low in cost, and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0026] Figure 1 The figure is the HPLC spectrum of the budesonide mother solution of the present invention.
[0027] Figure 2 This is the HPLC spectrum of the refined budesonide prepared in Example 1 of the present invention.
[0028] Figure 3 This is the HPLC spectrum of the refined budesonide prepared in Example 2 of the present invention.
[0029] Figure 4 This is the HPLC spectrum of the refined budesonide prepared in Example 3 of the present invention.
[0030] Figure 5 This is the HPLC spectrum of the refined budesonide prepared in Comparative Example 1 of the present invention. DETAILED DESCRIPTION
[0031] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.
[0032] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form also includes the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.
[0033] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0034] In the following examples and comparative examples, the HPLC (high performance liquid chromatography) pattern of budesonide mother solution is shown in Figure 1 .
[0035] Example 1
[0036] S1. Add 200 ml of 36.5% hydrochloric acid solution to 250 ml of dichloromethane and mix, cool to -2 to 0°C, add 50 g of budesonide mother liquor (isomer A 63%) to the solution, stir for 5 hours, add 500 ml of water, stir for 10 minutes, let stand for stratification, wash the lower organic layer once with 250 ml of water, separate the layers, wash once with 250 ml of 5% sodium bicarbonate solution, separate the layers, concentrate the organic layer of dichloromethane under reduced pressure, add 250 ml of isopropyl ether dropwise after concentrating to half the volume, continue to concentrate to a remaining volume of 200 ml, stir and cool to 0-5°C, crystallize for 1 hour, and discharge to obtain a refined product, 47 g.
[0037] S1. The purified product was heated and dissolved with 500 ml of methanol. After the solution was clear, the filtrate was concentrated under reduced pressure. The remaining volume was 100 ml and then cooled to 0-5°C. Crystallization was performed for 1 hour. The product was discharged to obtain 42 g of budesonide purified product. The yield was 84%. HPLC: 99.77%, isomer A: 44.4%, impurity L: 0.03%, impurity D: 0.03%. The HPLC spectrum of budesonide purified product is shown in Figure 2 .
[0038] Example 2
[0039] S1. Mix 300 ml of 36.5% hydrochloric acid solution with 50 ml of water, cool to -2 to 0°C, add 50 g of budesonide mother liquor (isomer A 63%) to the solution to dissolve, stir for 4 hours, add 1000 ml of water, stir for 10 minutes, add 300 ml of dichloromethane and stir for 10 minutes, let stand for stratification, wash the lower organic layer once with 250 ml of water, separate the layers, wash once with 250 ml of 5% sodium bicarbonate solution, separate the layers, concentrate the organic layer with dichloromethane under reduced pressure, add 250 ml of isopropyl ether dropwise after concentrating to half the volume, continue to concentrate to a remaining volume of 200 ml, stir and cool to 0-5°C, crystallize for 1 hour, and discharge to obtain a refined product, 46 g.
[0040] S2. The purified product was heated and dissolved with 500 ml of methanol. After the solution was clear, the filtrate was concentrated under reduced pressure. The remaining volume was 100 ml and then cooled to 0-5° C. for crystallization for 1 hour. The product was discharged to obtain 41 g of budesonide purified product with a yield of 82%. HPLC: 99.8%, isomer A: 47.1%, impurity L: 0.04%, impurity D: 0.06%. The HPLC spectrum of budesonide purified product is shown in Figure 3 .
[0041] Example 3
[0042] S1. Add 100 ml of perchloric acid solution to 250 ml of dichloromethane, cool to -2 to 0°C, add 50 g of budesonide mother liquor (isomer A 63%) to the solution, stir for 4 hours, add 500 ml of water, stir for 10 minutes, let stand for stratification, wash the lower organic layer once with 250 ml of water, separate the layers, wash once with 250 ml of 5% sodium bicarbonate solution, separate the layers, concentrate the organic layer of dichloromethane under reduced pressure, add 250 ml of isopropyl ether dropwise after concentrating to half the volume, continue to concentrate to a remaining volume of 200 ml, stir and cool to 0-5°C, crystallize for 1 hour, and discharge to obtain a refined product, 46 g.
[0043] S2. The purified product was heated and dissolved with 500 ml of methanol. After the solution was clear, the filtrate was concentrated under reduced pressure. The remaining volume was 100 ml and then the temperature was lowered to 0-5°C. Crystallization was performed for 1 hour. The product was discharged to obtain 41 g of budesonide purified product. The yield was 82%. HPLC: 99.84%, isomer A: 47.3%, impurity L: 0.06%, impurity D: 0.02%. The HPLC spectrum of budesonide purified product is shown in Figure 4 .
[0044] Example 4
[0045] This example is basically the same as Example 1, except that: in this example, dichloromethane is replaced by chloroform, and 40 g of refined budesonide is obtained with a yield of 80%, HPLC: 99.78%, isomer A: 48%, impurity L: 0.05%, and impurity D: 0.03%.
[0046] Comparative Example 1
[0047] S1. Add 50 g of budesonide mother liquor (isomer A 63%) to 600 ml of methanol, stir and heat to reflux, filter after dissolving, and concentrate the filtrate under reduced pressure to a volume of 150 ml. Cool to 0-10°C, crystallize for 2 hours, filter, and obtain a purified product, 39 g.
[0048] S2. Add the first refined product into 500 ml of methanol, stir and heat to reflux, filter after dissolving, and concentrate the filtrate under reduced pressure to a volume of 150 ml. Cool to 0-10°C, crystallize for 2 hours, filter, and obtain 31 g of budesonide refined product, HPLC: 99.3%, isomer A: 47.5%, impurity L: 0.22%, impurity D: 0.10%, HPLC spectrum of budesonide refined product is shown in Figure 5 The results showed that the yield of budesonide obtained by refining with methanol alone was low, and the impurities L and D were both high.
[0049] Comparative Example 2
[0050] This control example is basically the same as Example 1, except that: in this control example, dichloromethane is not added, and water is directly used for dilution after the reaction is completed. After the material is discharged, it is refined with methanol according to step S2.
[0051] The results showed that impurities D and L were not removed, indicating that impurities D and L could be removed by crystallization of dichloromethane with dropwise addition of isopropyl ether.
[0052] Comparative Example 3
[0053] This comparative example is basically the same as Example 1, except that in this comparative example, hydrochloric acid is replaced by glacial acetic acid, and the isomer A is still 60%.
[0054] The results show that hydrochloric acid was replaced but not converted. The conversion reaction requires a strong acid environment, and weak acid hardly reacts.
[0055] Comparative Example 4
[0056] This comparative example is basically the same as Example 1, except that in this comparative example, the reaction temperature is increased from -2 to 0°C to 20-25°C, the product contains more impurities, and the yield is 70%.
[0057] The results show that the reaction temperature needs to be low, otherwise the product quality and yield will be affected.
[0058] In summary, the treatment method of the present invention effectively converts the diastereomer A into the diastereomer B under acidic conditions, and processes the budesonide mother liquor into a qualified budesonide refined product through a chloroalkane organic solvent and an isopropyl ether crystallization system; the product obtained by the treatment method of the present invention has high purity, few impurities, and high recovery efficiency, and its HPLC content reaches more than 99.0%, any impurity is less than 0.10%, the isomer A is 40-51%, and the yield is more than 80%; the treatment method of the present invention is simple to operate, energy-saving and consumption-reducing, green and environmentally friendly, low in cost, and is conducive to industrial production.
[0059] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements 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 treating a budesonide mother solution, characterized in that: The steps include: S1, adding budesonide mother liquor to chloroalkane organic solvent and inorganic acid solution, stirring and standing to separate, washing the organic layer with water and sodium bicarbonate until neutral, concentrating the organic solvent, then adding isopropyl ether dropwise, cooling and crystallizing, filtering, and obtaining a primary refined product; S2. adding the primary refined product into an alcohol solvent to heat and dissolve, filtering after dissolving, concentrating the filtrate under reduced pressure, cooling and crystallizing, filtering, and obtaining a refined budesonide product.
2. The method for treating budesonide mother solution according to claim 1, characterized in that: In step S1, the chloroalkane organic solvent includes one or more of dichloromethane and chloroform.
3. The method for treating budesonide mother solution according to claim 1, characterized in that: In step S1, the inorganic acid solution includes: one or more of hydrochloric acid and perchloric acid.
4. The method for treating budesonide mother solution according to claim 1, characterized in that: In step S1, the sodium bicarbonate is a 5% sodium bicarbonate solution.
5. The method for treating budesonide mother solution according to claim 1, characterized in that: In step S1, the feeding ratio of the budesonide mother liquor, the chloroalkane organic solvent, the inorganic acid, the sodium bicarbonate and the isopropyl ether is 1:(5-10):(2.0-6.0):(0.1-0.5):(2-5), wherein the budesonide mother liquor and the sodium bicarbonate are measured in g, and the chloroalkane organic solvent, the inorganic acid and the isopropyl ether are measured in mL.
6. The method for treating budesonide mother solution according to claim 1, characterized in that: Step S1 comprises: cooling the chloroalkane organic solvent and the inorganic acid solution to -2 to 0°C, adding budesonide mother liquor to the solution, stirring for 3-6 hours, adding water and stirring, standing to separate layers, washing the organic layer once with water, separating layers, washing once with a sodium bicarbonate solution, separating layers, concentrating the organic solvent, adding isopropyl ether dropwise after concentrating to half the volume, continuing to concentrate, stirring and cooling to 0-5°C for crystallization, and filtering to obtain a primary refined product.
7. The method for treating budesonide mother solution according to claim 1, characterized in that: In step S2, the feed ratio of the primary refined product to the alcohol solvent is 1:(10.0-15.0), wherein the primary refined product is measured in g and the alcohol solvent is measured in mL.
8. The method for treating budesonide mother solution according to claim 1, characterized in that: In step S2, the alcohol solvent is methanol.
9. The method for treating budesonide mother solution according to claim 1, characterized in that: Step S2 comprises: adding the primary refined product into methanol to heat and dissolve, filtering after dissolving, concentrating the filtrate under reduced pressure, cooling to 0-5° C. for crystallization, filtering, and obtaining a refined budesonide product.
10. A refined budesonide product, characterized in that: The budesonide mother solution is prepared by the treatment method of any one of claims 1 to 9.