CN114195847B - Prednisolone and preparation method thereof - Google Patents
Prednisolone and preparation method thereof Download PDFInfo
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- CN114195847B CN114195847B CN202111534594.0A CN202111534594A CN114195847B CN 114195847 B CN114195847 B CN 114195847B CN 202111534594 A CN202111534594 A CN 202111534594A CN 114195847 B CN114195847 B CN 114195847B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to the technical field of chemical pharmacy, in particular to prednisolone and a preparation method thereof, wherein the preparation method comprises the following steps: taking a prednisolone intermediate reduced product as a raw material, and deprotecting 3-and 20-semicarbazones under a strong acid/sodium nitrite system to obtain prednisolone; wherein the reaction system also comprises a halogenated hydrocarbon/ester mixed solvent. According to the invention, a proper mixed solvent is added in the deprotection reaction process of the prednisolone intermediate reducing substance, so that the deprotection reaction is subjected to dynamic reaction and mass transfer in a water phase and an organic phase, the target product enters the organic phase at the first time, the prednisolone is greatly prevented from being damaged by a strong acid strong oxidant, the reaction is pushed to be carried out in the positive direction, the occurrence of side reactions is reduced, and the yield and the quality are finally improved. The mass yield of the prednisolone obtained by the preparation method is more than 72 percent (the theoretical mass yield of the prednisolone relative to a reducing substance is 76.3 percent), the HPLC content reaches more than 99.4 percent, and the content of single impurities is less than 0.10 percent.
Description
Technical Field
The invention relates to the technical field of chemical pharmacy, in particular to prednisolone and a preparation method thereof.
Background
Prednisolone (Prednisonone), the chemical name of which is 11 beta, 17,21-trihydroxy pregna-1,4-diene-3,20-dione, is a very important steroid hormone raw material drug, and can be further synthesized into a plurality of high value-added raw material drugs including Prednisolone sodium phosphate, prednisolone valerate acetate and the like.
The Chinese, american and European pharmacopoeias are loaded at present, act on sugar metabolism, have certain influence on electrolyte metabolism, can relieve pathological reaction of organism tissues to destructive stimulation, and are used for treating allergic diseases such as severe bronchial asthma and severe dermatitis, and diseases such as active rheumatism, rheumatoid arthritis and lupus erythematosus.
In the prior art, the traditional preparation method of prednisolone comprises biological transformation and chemical synthesis.
The biotransformation route is as follows:
the first chemical synthesis route:
chemical synthesis route two:
the biological fermentation route is prepared by taking hydrocortisone as a substrate and carrying out 1,2-position dehydrogenation through arthrobacter fermentation, and the preparation method has the defects of low substrate feeding concentration, long conversion period, low separation and purification efficiency and the like.
China patents CN200710061258.2 and CN201310348285.3 adopt a chemical synthesis route I to prepare prednisolone. The technical key point is that 9, 11-position functional groups and 21-position functional groups are reformed, 9-halogen-11-position hydroxylate is firstly obtained, then dehalogenation is carried out through a metal reducing agent, and a target product prednisolone is obtained through iodine replacement and hydrolysis. The main problems are that heavy metal chromium or zinc is used in the dehalogenation process, and auxiliary materials such as thioglycollic acid and the like which contain sulfur and have strong irritation are used, so that the dehalogenation process is extremely unfavorable for the environment.
The chinese patent CN00136583.5 adopts a second chemical synthesis route to prepare the prednisolone intermediate reduced product, but does not mention any deprotection reaction system and the yield and quality information of the target product prednisolone.
The difference between the chinese patent CN201510787831.2 and the second chemical synthesis route is that esterification is performed on 21 position after reduction, and then deprotection is performed to obtain prednisolone acetate first, and then hydrolysis is performed to obtain the target product prednisolone. Compared with the second chemical synthesis route, the two procedures of esterification and hydrolysis are added, the process design is complex, auxiliary materials and production period are increased, and the industrial production is not facilitated.
Therefore, in view of the above problems, it is an urgent technical problem to be solved by those skilled in the art to develop a novel method for preparing prednisolone.
Disclosure of Invention
The invention aims to provide a preparation method of prednisolone, which remarkably improves the yield and quality of prednisolone.
The invention provides a preparation method of prednisolone, which comprises the following steps:
taking a prednisolone intermediate reduced product as a raw material, and deprotecting 3-and 20-semicarbazones under a strong acid/sodium nitrite system to obtain prednisolone;
wherein the reaction system also comprises a halogenated hydrocarbon/ester mixed solvent.
The reaction process of deprotection in the chemical synthesis route II in the prior art is as follows:
reaction formula 1:
reaction formula 2:
reaction formula 3:
reaction formula 4:
as can be seen from the above reaction sequence, the target product is already liberated in the first step, and the whole deprotection process is carried out in an environment of strong acid and strong oxidation. For prednisolone corticoid substances, the environment with strong acid and strong oxidizing property has great destructive effect on the prednisolone corticoid substances, so that the yield and the quality of the products are not ideal when the deprotection reaction is carried out in the system.
In order to solve the problems, the invention adds a proper mixed solvent in the process of the deprotection reaction of the prednisolone intermediate reduction substance to ensure that the deprotection reaction carries out dynamic reaction and mass transfer in a water phase and an organic phase, and a target product enters the organic phase at the first time, thereby greatly avoiding the prednisolone from being damaged by a strong acid strong oxidant, promoting the reaction to be carried out in the positive direction, reducing the occurrence of side reactions and finally improving the yield and the quality.
Preferably, the technical scheme comprises the following steps:
s1, adding a prednisolone intermediate reduced product into strong acid, then adding a halogenated hydrocarbon/ester mixed solvent, slowly dropwise adding a sodium nitrite solution, and carrying out heat preservation reaction to obtain prednisone Long Cupin;
and S2, extracting the crude prednisolone product by using a halogenated hydrocarbon/ester mixed solvent, and carrying out reduced pressure distillation on an organic layer to obtain the prednisolone.
The deprotection reaction of the present invention comprises the steps of: adding the reduced matter into strong acid solution, stirring to dissolve, adding mixed solvent of halohydrocarbon and ester, slowly dripping sodium nitrite solution, heat-insulating and reacting
And (3) after the reaction is finished, separating a water layer, extracting the water layer by using a halogenated hydrocarbon/ester mixed solvent with a certain proportion, combining organic layers, and distilling under reduced pressure to obtain the target product prednisolone.
In the deprotection reaction, the target product prednisolone can enter the halogenated hydrocarbon/ester mixture for the first time
In the solvent synthesis, on one hand, the reaction process is accelerated, and on the other hand, the target product is greatly prevented from being damaged by strong acid and strong oxidant.
Preferably, in this embodiment, the mass-to-volume ratio of the prednisolone intermediate reduced product, the strong acid, and the sodium nitrite is 1w:2v: (1-1.2 w).
Specifically, in the deprotection reaction, the mass-to-volume ratio of the prednisolone intermediate reducing substance, the strong acid and the sodium nitrite is 1w:2v: (1-1.2 w), and preferably 1w:2v:1w.
Preferably, in this embodiment, the prednisolone intermediate reduced product and the halogenated hydrocarbon/ester
The mass volume ratio of the similar mixed solvent is 1w: (8-10 v) of the total weight of the composition,
wherein in the halogenated hydrocarbon/ester mixed solvent, the volume ratio of the halogenated hydrocarbon to the ester is 1: (0.8-3).
The halogenated hydrocarbon/ester mixed solvent is mainly used for providing inertia for deprotection reaction
The organic environment is convenient for protecting the target product, and therefore, the dosage of the halogenated hydrocarbon/ester mixed solvent is not particularly limited.
However, in order to reduce the production cost and improve the product utilization rate, the mass-to-volume ratio of the prednisolone intermediate reductant to the halogenated hydrocarbon/ester mixed solvent is 1w: (8-10 v), and in the halogenated hydrocarbon/ester mixed solvent, the volume ratio of the halogenated hydrocarbon to the ester is 1: (0.8-3).
Preferably, in step S1, the strong acid is hydrochloric acid;
5, the halogenated hydrocarbon is any one or two of dichloromethane or trichloromethane;
the esters are either one or two of ethyl acetate or butyl acetate.
Specifically, the strong acid is a substance that can decompose protonic acid, and is preferably hydrochloric acid.
According to the principle of similar solubility parameters, the selected halogenated hydrocarbon is either or both of dichloromethane (delta = 9.7) or trichloromethane (delta = 9.3), and the ester is either or both of ethyl acetate (delta = 9.1) or butyl acetate (delta = 8.2).
Preferably, in the step S1, the dropping time of the sodium nitrite solution is controlled to be 8-12h, and the heat preservation reaction is controlled to be 10-14h.
In order to further prevent the product prednisolone from being oxidized by the strong oxidant, the sodium nitrite is added into the reaction system in a dropwise manner, the dropwise addition time is preferably 10 hours, and the heat preservation reaction is controlled to be 12 hours.
Preferably, in the technical scheme, the mass concentration of the hydrochloric acid is 36%, and the mass concentration of the sodium nitrite is 15-25%.
Preferably, in the present technical solution, step S2 specifically includes: and after the heat preservation reaction is finished, fully stirring for 0.5-1.5h, standing for layering, extracting a water phase by using a halogenated hydrocarbon/ester mixed solvent, combining organic layers, and distilling under reduced pressure to obtain the prednisolone.
Specifically, the post-treatment process comprises the steps of fully stirring for 0.5-1.5h after the heat preservation reaction is finished, standing for layering, wherein the volume ratio of a water phase is 1: (0.8-3), extracting with a mixed solvent of dichloromethane and ethyl acetate, combining organic layers, washing the organic layers with water, decoloring, filtering, distilling under reduced pressure, cooling, discharging, and drying to obtain prednisolone.
In this embodiment, it is preferable that the organic layer is decolorized and filtered before the distillation under reduced pressure in step S2.
The prednisolone prepared by the method also belongs to the protection scope of the invention, and specifically, the yield of the prednisolone is more than 72%, the purity is more than 99.4%, and the content of single impurity is less than 0.1%.
Compared with the prior art, the preparation method of prednisolone of the invention has the following advantages:
according to the invention, a proper mixed solvent is added in the deprotection reaction process of the prednisolone intermediate reducing substance, so that the deprotection reaction is subjected to dynamic reaction and mass transfer in a water phase and an organic phase, and a target product enters the organic phase at the first time, so that the prednisolone is greatly prevented from being damaged by a strong acid strong oxidant, the reaction is pushed to be carried out in the positive direction, the occurrence of side reactions is reduced, and the yield and the quality are finally improved.
The mass yield of the prednisolone obtained by the preparation method is more than 72 percent (the theoretical mass yield of the prednisolone relative to a reducing substance is 76.3 percent), the HPLC content reaches more than 99.4 percent, and the content of single impurities is less than 0.10 percent. Therefore, the prednisolone prepared by the preparation method has obvious competitiveness in quality and yield.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, 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 belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms also include the plural forms unless the context clearly dictates otherwise, and further, it is understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of the stated features, steps, operations, devices, components, and/or combinations thereof.
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The prednisolone intermediate reduced product used in the invention is prepared by self, wherein the solid material is measured by g (grams) and expressed by material (g), and the liquid material is measured by ml (milliliters) and expressed by material (ml).
HPLC refers to high performance liquid chromatography.
Example 1
S11, sequentially adding 100ml of hydrochloric acid with the mass percentage concentration of 36% and 50g of reducing substances into a reaction bottle, stirring at 20-30 ℃ for 30min to dissolve, then respectively adding 100ml of dichloromethane and 300ml of ethyl acetate, slowly dropwise adding a solution prepared from 50g of sodium nitrite and 250ml of water, finishing dropwise adding for 10h, and carrying out heat preservation reaction for 12h.
S12, fully stirring for 0.5h after the reaction is finished, standing for layering, extracting a water phase by using a mixed solvent of 20ml of dichloromethane and 60ml of ethyl acetate, combining organic layers, washing the organic layer by using 50ml of water, decoloring, filtering, distilling under reduced pressure, cooling, discharging, drying to obtain prednisolone 36g, wherein the HPLC purity is 99.4%,
maximum single impurity 0.05%.
Example 2
S21, sequentially adding 200ml of hydrochloric acid with the mass percent concentration of 36% and 200ml of hydrochloric acid with the mass percent concentration of 36% into a reaction bottle
100g of reducing substance is stirred for 30min at the temperature of 20-30 ℃ to be dissolved and cleared, then 300ml of dichloromethane and 600ml of ethyl acetate are respectively added, solution prepared by 100g of sodium nitrite and 500ml of water is slowly dripped,
after the dropwise addition is finished for 10h, the reaction is carried out for 12h under the condition of heat preservation.
S22, fully stirring for 1.5h after the reaction is finished, standing for layering, extracting an aqueous phase by using a mixed solvent of 60ml of dichloromethane and 120ml of ethyl acetate, combining organic layers, washing the organic layer by using 100ml of water,
decolorizing, filtering, vacuum distilling, cooling, discharging and drying to obtain prednisolone 72.2g, HPLC purity 99.5% and maximum single impurity 0.04%.
Example 3
S31, sequentially adding 100ml of hydrochloric acid with the mass percentage concentration of 36% and 50g of reducing substances into a reaction bottle, stirring at 20-30 ℃ for 30min to dissolve, and then respectively adding 250ml of trichloromethane
And 200ml of butyl acetate, slowly dropwise adding a solution prepared from 60g of sodium nitrite and 300ml of water, finishing dropwise adding for 10 hours, and carrying out heat preservation reaction for 12 hours.
S32, fully stirring for 1h after the reaction is finished, standing for layering, extracting a water phase by using a mixed solvent of 50ml of trichloromethane and 40ml of butyl acetate, combining organic layers, washing the organic layers by using 50ml of water, decoloring and filtering, carrying out reduced pressure distillation, cooling, discharging and drying to obtain 36.3g of prednisolone, wherein the HPLC purity is 99.5 percent, and the maximum single impurity content is 0.04 percent.
Example 4
S41, sequentially adding 200ml of hydrochloric acid with the mass percentage concentration of 36% and 100g of reducing substances into a reaction bottle, stirring at 20-30 ℃ for 30min to dissolve, then respectively adding 500ml of dichloromethane and 500ml of ethyl acetate, slowly dropwise adding a solution prepared from 120g of sodium nitrite and 600ml of water, finishing dropwise adding after 10 hours, and carrying out heat preservation reaction for 12 hours.
S42, after the reaction is finished, fully stirring for 1.5h, standing for layering, extracting a water phase by using a mixed solvent of 100ml of dichloromethane and 100ml of ethyl acetate, combining organic layers, washing the organic layer by using 100ml of water, decoloring and filtering, carrying out reduced pressure distillation, cooling, discharging, and drying to obtain 72.3g of prednisolone, wherein the HPLC purity is 99.6 percent, and the maximum single impurity content is 0.03 percent.
Table 1 examples 1-4 product purity and yield
The data in table 1 show that the prednisolone prepared by the preparation method has the mass yield of over 72 percent, the HPLC content of over 99.4 percent and the content of single impurity of less than 0.10 percent. Therefore, the quality and yield of the prednisolone prepared by the preparation method of the invention have obvious competitiveness.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (7)
1. The preparation method of prednisolone is characterized by comprising the following steps:
taking a prednisolone intermediate reduced product as a raw material, and deprotecting 3-and 20-semicarbazones under a strong acid/sodium nitrite system to obtain prednisolone;
wherein the reaction system also comprises a halogenated hydrocarbon/ester mixed solvent;
the method comprises the following steps:
s1, adding a prednisolone intermediate reduced substance into strong acid, then adding a halogenated hydrocarbon/ester mixed solvent, slowly dropwise adding a sodium nitrite solution, and carrying out heat preservation reaction to obtain prednisone Long Cupin;
s2, extracting the crude prednisolone product by using a halogenated hydrocarbon/ester mixed solvent, and carrying out reduced pressure distillation on an organic layer to obtain prednisolone;
the mass volume ratio of the prednisolone intermediate reductant to the halogenated hydrocarbon/ester mixed solvent is 1w: (8-10 v) of the total weight of the composition,
wherein, in the halogenated hydrocarbon/ester mixed solvent, the volume ratio of the halogenated hydrocarbon to the ester is 1: (0.8-3);
in step S1, the strong acid is hydrochloric acid;
the halogenated hydrocarbon is one or two of dichloromethane or trichloromethane;
the esters are either one or two of ethyl acetate or butyl acetate.
2. The method according to claim 1, wherein the mass-to-volume ratio of the prednisolone intermediate reduced product, the strong acid, and the sodium nitrite is 1w:2v: (1-1.2 w).
3. The preparation method according to claim 1, wherein in the step S1, the dropping time of the sodium nitrite solution is controlled to be 8-12 hours, and the heat-insulating reaction is controlled to be 10-14 hours.
4. The production method according to claim 1, wherein the mass concentration of the hydrochloric acid is 36% and the mass concentration of the sodium nitrite is 15 to 25%.
5. The method according to claim 1, wherein step S2 specifically comprises: and after the heat preservation reaction is finished, fully stirring for 0.5-1.5h, standing for layering, extracting a water phase by using a halogenated hydrocarbon/ester mixed solvent, combining organic layers, and distilling under reduced pressure to obtain the prednisolone.
6. The process according to claim 1, wherein the organic layer is subjected to decoloring filtration before the distillation under reduced pressure in step S2.
7. Prednisolone prepared by the preparation method of any one of claims 1-6, wherein the yield of prednisolone is greater than 72%, the purity is greater than 99.4%, and the content of single impurity is less than 0.1%.
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Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3079409A (en) * | 1958-12-31 | 1963-02-26 | Merck & Co Inc | Hydrolysis of 3-semicarbazido steroids |
| CN1159334C (en) * | 2000-12-27 | 2004-07-28 | 天津药业集团有限公司 | Production process of prednisolone Acetate condensating reduced product |
| CN102146113B (en) * | 2010-02-08 | 2014-04-16 | 仙居县力天化工有限公司 | Method for synthesizing 16 alpha-hydroxy prednisolone |
| CN102827231A (en) * | 2012-09-25 | 2012-12-19 | 河南利华制药有限公司 | Process for preparing hydrocortisone |
| CN105503986A (en) * | 2015-11-17 | 2016-04-20 | 华中药业股份有限公司 | Prednisolone acetate preparation method |
| CN105384790A (en) * | 2015-11-17 | 2016-03-09 | 华中药业股份有限公司 | Preparation method of prednisolone |
| CN105367618A (en) * | 2015-11-17 | 2016-03-02 | 华中药业股份有限公司 | Method for preparing hydrocortisone |
| CN105294800A (en) * | 2015-11-17 | 2016-02-03 | 华中药业股份有限公司 | Preparation method for hydrocortisone acetate |
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