CN108070013B - Process for the preparation of 21-halogenated steroids - Google Patents
Process for the preparation of 21-halogenated steroids Download PDFInfo
- Publication number
- CN108070013B CN108070013B CN201810060392.9A CN201810060392A CN108070013B CN 108070013 B CN108070013 B CN 108070013B CN 201810060392 A CN201810060392 A CN 201810060392A CN 108070013 B CN108070013 B CN 108070013B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- halogenated
- reaction
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Abstract
A process for the preparation of a 21-halogenated steroid comprising the steps of: the compound of formula I is used as raw material, firstly, in the mixed solvent of organic solvent and water, the compound and halogenated reagent produce 21-bit halogenation reaction, then the compound and halogenated reagent produce hydrolysis reaction under the acidic condition so as to obtain the 21-halogenated steroid compound of formula II. The preparation method is simple, mild in condition, wide in applicability to the target product 21-halogenated steroid compound shown in the formula II, high in yield of the 21-halogenated steroid compound and high in purity, and the problems of long synthesis route and low yield of the traditional method are solved.
Description
Technical Field
The invention relates to the technical field of steroid compound preparation, in particular to a preparation method of a 21-halogenated steroid compound.
Background
Adrenocortical hormone is a very important class of steroid hormone drug molecules, including cortisone, betamethasone, dexamethasone and other products, all of which have 21-substituent groups, the most common compounds have 21-hydroxy groups, such as hydrocortisone, betamethasone, fluocinonide and the like, and dexamethasone sodium phosphate, betamethasone dipropionate, betamethasone valerate and the like can be further derived, all of which are synthesized from 21-halogenated intermediates, and some of which have 21-halogenated groups in the structure, such as clobetasol, mometasone furoate, halcinonide and the like, all of which have 21-chloro groups. Therefore, the synthesis of 21-halogenated steroids is very important.
In the traditional synthetic route of 21-halogenated steroid compounds, 21-halogenation is generally obtained by substitution reaction of 21 hydrogen by halogen monomers, generally limited to iodine simple substances or bromine simple substances, and the method has the problems of multiple substitution phenomena, poor selectivity, low yield, potential production safety hazards and the like. For example, betamethasone is taken as an example, the conventional 21-iodo process comprises the following steps of substituting iodine with simple substance, esterifying the substituted iodine under the condition of potassium acetate, and hydrolyzing to obtain 21-OH, wherein the conventional processes of other steroid drug molecules are basically similar to the above steps:
it has also been reported that 21-bromosteroid compounds are obtained by bromination, but the use of bromine is too reactive, and is prone to act on other double bonds or active sites, resulting in more side reactions and lower yields. The process for synthesizing 21-chloro steroids is more complicated, and many reports firstly sulfonylate 21-OH and then chlorinate to convert into 21-chlorine, and the process steps are longer and need to start from the existing 21-hydroxyl.
A method for directly synthesizing the halobetasol by introducing a side chain and constructing a 21-chloro group simultaneously is also reported, and the method is novel, short in step and high in yield, but needs a highly toxic cyanide and a special silicon reagent, and is complex in reaction process.
Disclosure of Invention
Accordingly, there is a need for a process for preparing 21-halogenated steroids in a simple procedure and in high yield and purity.
A process for the preparation of a 21-halogenated steroid comprising the steps of:
taking a compound shown in a formula I as a raw material, firstly carrying out 21-site halogenation reaction with a halogenating reagent in a mixed solvent of an organic solvent and water, and then carrying out hydrolysis reaction under an acidic condition to obtain a 21-halogenated steroid compound shown in a formula II; the structural formulas of the compound of formula I and the 21-halogenated steroid of formula II are respectively as follows:
wherein the dotted line position represents a single bond or a double bond;
R1is carbonyl or OH;
R2is H, CH3Cl or F;
R3is H, F, Cl, OH or no radical, R4Is carbonyl, OH or H; or, R3And R4Is an epoxy group;
R5is H, α -CH3Or β -CH3；
R6Is H, Si (CH)3)3、COCH3、COCH2CH3；
R7Is Si (CH)3)3、COCH3、COCH2CH3、CH3Or CH2CH3；
X is halogen.
The preparation method is simple, mild in condition, wide in applicability to the target product 21-halogenated steroid compound shown in the formula II, high in yield of the 21-halogenated steroid compound and high in purity, and the problems of long synthesis route and low yield of the traditional method are solved, so that the yield is improved, and the energy consumption is reduced. In addition, the preparation method has stable yield.
In one embodiment, the halogenation reaction is carried out for 1-4 h at-10-30 ℃ in the presence of an alkaline stabilizer.
In one embodiment, the basic stabilizer is at least one selected from triethylamine, pyridine, sodium carbonate and sodium hydroxide.
In one embodiment, the ratio of the amount of the basic stabilizer to the amount of the compound of formula I is 0.1 to 1: 1.
In one embodiment, the halogenating agent is selected from at least one of bromosuccinimide, chlorosuccinimide, iodosuccinimide, dibromohydantoin, dichlorohydantoin, hypochlorous acid, sodium hypochlorite, hypobromous acid, and sodium hypobromoate.
In one embodiment, the ratio of the amount of the halogenated agent to the amount of the substance of the compound of formula I is 1-4: 1.
In one embodiment, the halogenating agent is chlorosuccinimide and the ratio of the amount of the halogenating agent to the material of the compound of formula i is 1.2: 1.
In one embodiment, the hydrolysis reaction is carried out at 0-60 ℃ for 1-2 h.
In one embodiment, the pH value of the acidic condition of the hydrolysis reaction is 1-4.
In one embodiment, the method further comprises the step of purifying the 21-halogenated steroid by: and adding alkali into the reaction liquid after the hydrolysis reaction to adjust the pH value to be neutral, concentrating the solvent, adding water, cooling to 0-10 ℃, stirring for 1-2 h for crystallization, filtering, and washing with water.
Detailed Description
In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
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 invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
A process for preparing a 21-halo steroid compound according to one embodiment includes the steps of:
the compound of formula I is used as raw material, firstly, in the mixed solvent of organic solvent and water, the compound and halogenated reagent produce 21-bit halogenation reaction, then the compound and halogenated reagent produce hydrolysis reaction under the acidic condition so as to obtain the 21-halogenated steroid compound of formula II.
The structural formulae of the compounds of formula I and the 21-halogenated steroids of formula II are shown below:
wherein the dotted line position represents a single bond or a double bond;
R1is carbonyl or OH;
R2is H, CH3Cl or F;
R3is H, F, Cl, OH or no radical, R4Is carbonyl, OH or H; or, R3And R4Is an epoxy group;
R5is H, α -CH3Or β -CH3；
R6Is H, Si (CH)3)3、COCH3、COCH2CH3；
R7Is Si (CH)3)3、COCH3、COCH2CH3、CH3Or CH2CH3；
X is halogen.
The preparation method is simple, mild in condition, wide in applicability to the target product 21-halogenated steroid compound shown in the formula II, high in yield of the 21-halogenated steroid compound and high in purity, and the problems of long synthesis route and low yield of the traditional method are solved, so that the yield is improved, and the energy consumption is reduced. In addition, the preparation method has stable yield.
The yield of the 21-halogenated steroid compound prepared by the preparation method is as high as 95.6 percent, and the purity is as high as 98 percent.
The preparation method uses a halogenating reagent to act on the double bonds of 20 and 21 of the compound shown in the formula I, and 21-halogenated steroid compound is generated after acidolysis and hydrolysis. The 17-oxygen atom synergistic effect enables the halogenation reaction to have higher selectivity, thereby enabling the selectivity of the product to be high. The reaction mechanism of the preparation method is simplified as follows:
it is worth mentioning that the first-mentioned type of the coating,R2is H, CH3Cl or F; and R is2In the case of Br, the reaction is unstable when hydrolysis reaction occurs, and 6,7 double bond or 6-hydroxy group is formed, so that impurities are formed, resulting in a decrease in yield.
It will be appreciated that the compounds of formula I are commercially available or may be synthesized by reaction. In one embodiment, the compound of formula I is obtained by enolizing the carbonyl group at position 20 of the compound of formula III, or by constructing the side chain at position 17 from the compound of formula IV. The structural formulas of the compound of formula III and the compound of formula IV are shown as follows:
it is understood that when the 9 and 11 positions are single bonds, R is4Is carbonyl or OH, R3Is H, F, Cl, OH, or R3,R4Is epoxy. Since the alkene alcohol is less stable, R is a double bond at the 9,11 position4Is H, R3Is free of radicals.
In one embodiment, R1The double bonds at the 1,2 positions are double bonds, and the double bonds at the 1,2 positions and the 4,5 positions react with the carbonyl at the 3 position to form a stable conjugated structure, so that the α -H activity is obviously reduced, and no side reaction occurs.
In one embodiment, Br, Cl or I. By adopting the preparation method, various halogenated products of Br, Cl or I can be prepared, the problems of low selectivity and yield of the traditional preparation method for preparing 21-iodo steroid and more side reactions and low yield of the preparation of 21-bromo steroid are avoided, and the applicability of the substrate is improved.
In one embodiment, the halogenation reaction is carried out for 1-4 h at-10-30 ℃ in the presence of an alkaline stabilizer. Preferably, the temperature of the halogenation reaction is 0-5 ℃.
In one embodiment, after the end of the halogenation reaction is detected by TLC, the method also comprises the step of adding a reducing agent to quench the reaction. Specifically, the reducing agent is sodium sulfite or sodium thiosulfate, etc., to quench the excess halogenating agent and prevent the production of by-products.
Preferably, the basic stabilizer is at least one selected from triethylamine, pyridine, sodium carbonate and sodium hydroxide. The ratio of the amount of the alkaline stabilizer to the amount of the compound of formula I is 0.1-1: 1.
In one embodiment, the halogenating agent is selected from at least one of bromosuccinimide (NBS), chlorosuccinimide (NCS), iodosuccinimide (NIS), dibromohydantoin, dichlorohydantoin, hypochlorous acid, sodium hypochlorite, hypobromous acid, and sodium hypobromous acid. Preferably, the ratio of the amount of the halogenating agent to the amount of the substance of the compound of formula I is 1-4: 1.
Preferably, the halogenating agent is chlorosuccinimide and the ratio of the amount of halogenating agent to the amount of substance of the compound of formula i is 1.2: 1.
In one embodiment, the hydrolysis reaction is carried out at 0-60 ℃ for 1-2 h. Preferably, the temperature of the hydrolysis reaction is 25-30 ℃.
Specifically, the pH value of the acidic condition of the hydrolysis reaction is 1-4. Optionally, the acid used to adjust the pH is at least one of hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, perchloric acid, camphorsulfonic acid, trifluoroacetic acid, and glacial acetic acid. Preferably, 36 wt% concentrated hydrochloric acid is used. Preferably, the pH value of the acidic condition of the hydrolysis reaction is 1-2.
In one embodiment, the organic solvent is selected from at least one of acetone, Tetrahydrofuran (THF), methanol, ethanol, isopropanol, dioxane, and N, N-Dimethylformamide (DMF). Specifically, the volume ratio of the organic solvent to the water is 1-20: 1.
Preferably, the volume ratio of organic solvent to water is 5: 1.
In one embodiment, the method further comprises the step of purifying the 21-halogenated steroid: and adding alkali into the reaction liquid after the reaction to adjust the pH value to be neutral, concentrating the solvent, adding water, cooling to 0-10 ℃, stirring for 1-2 h, crystallizing, filtering, and washing with water.
The following are specific examples.
Example 1
Adding 100g (0.364mol) of compound Ia, 5mL (0.036mol) of triethylamine, 500mL of acetone and 100mL of water into a three-neck flask with a thermometer and a stirring magneton, uniformly stirring, cooling a system to 0-5 ℃, slowly adding 40g (0.300mol) of NCS into the reaction flask in batches, keeping the temperature at 0-5 ℃ in the process, adding the NCS in 5 batches, adding the NCS once every 20min, keeping the temperature and stirring for 1-2 h after the addition is finished. And (3) detecting that the reaction raw materials completely disappear by TLC (benzene: acetone is 6:1), stopping the reaction, dropwise adding 100mL of 20 wt% sodium sulfite solution to quench the reaction, adding 30mL of 36 wt% concentrated hydrochloric acid, adjusting the pH to about 2, heating the system to 25-30 ℃, continuing the reaction for 1-3 h, detecting hydrolysis by TLC, and dropwise adding 20% NaOH solution to adjust the system to be neutral. Decompressing and concentrating to remove acetone, adding 500mL of water for water precipitation, stirring for 30min at 0-10 ℃, filtering, washing a filter cake with a proper amount of water, and drying at 50-60 ℃ to obtain 101g of a compound IIa. The yield is 95.6 percent, and the purity is more than 98 percent. Where the yield is the percentage value of the actual product mass relative to the theoretical product mass corresponding to the compound of the formula Ia used, the following examples are similar.
Example 2
Adding 100g (0.314mol) of compound Ib, 500mL of acetone, 100mL of water and 5g (0.047mol) of sodium carbonate into a three-neck flask with a thermometer and a stirring magneton, uniformly stirring, cooling the system to 5-10 ℃, slowly adding 40g (0.300mol) of NCS into the reaction flask in batches, keeping the temperature at 5-10 ℃ in the process, adding the NCS in 5 batches, adding the NCS once every 20min, keeping the temperature and stirring for 1-2 h after the addition is finished. And (3) detecting that the reaction raw materials completely disappear by TLC (benzene: acetone is 6:1), stopping the reaction, adding 20g of sodium sulfite solid, quenching the reaction, stirring for 30min, dropwise adding 30mL of 36 wt% concentrated hydrochloric acid, adjusting the pH of the system to 1, heating to 30-40 ℃, continuing the reaction for 1-3 h, detecting hydrolysis by TLC, and dropwise adding 20% NaOH solution to adjust the system to be neutral. Concentrating under reduced pressure to remove acetone, adding 500mL of water for water precipitation, stirring at 0-10 deg.C for 30min, filtering, washing filter cake with appropriate amount of water, and drying at 50-60 deg.C to obtain compound IIb, 92 g. The yield is 93.8 percent, and the purity is more than 97 percent.
Example 3
Adding 50g (0.165mol) of compound ic, 5mL (0.036mol) of triethylamine, 500mL of acetone and 80mL of water into a three-neck flask with a thermometer and a stirring magneton, uniformly stirring, cooling a system to 0-5 ℃, slowly adding 30g (0.105mol) of dibromohydantoin into the reaction flask in batches, keeping the temperature at 0-5 ℃ in the process, adding the dibromohydantoin in 5 batches, adding the dibromohydantoin once every 20min, keeping the temperature for 0-5 ℃, and stirring for 1 h. TLC (detection by TLC) detects that the reaction raw material completely disappears (benzene: acetone is 4:1), the reaction is stopped, 100mL of 20% sodium sulfite solution is dripped to quench the reaction, 30mL of 36 wt% concentrated hydrochloric acid is added, the pH of the system is adjusted to 2, the temperature is increased to 25-30 ℃, the reaction is continued for 1-2 h, after TLC detection, 20 wt% Na is dripped2CO3The solution adjusted the system to neutral. And directly adding 1000mL of water for elutriation, stirring for 30min at 0-10 ℃, filtering, washing a filter cake with a proper amount of water, and drying at 35-45 ℃ to obtain 96g of a compound IIc. The yield is 85 percent, and the purity is more than 95 percent.
Example 4
Example 4 is essentially the same as example 1, except for the starting compounds and the reaction temperature, which differs from compound Ia in that the carbonyl group at the 3-position is replaced by a hydroxyl group and the 6-position is replaced by Cl; the temperature of the halogenation reaction is-10 to-5 ℃, and the temperature of the hydrolysis reaction is 55 to 60 ℃. The yield was 82% and the purity was 93%.
Example 5
Example 5 is essentially the same as example 1, except for the starting compounds and the reaction temperature, which differ from compound Ia in that the hydroxyl group at position 17 is replaced by OSi (CH)3)3Replacement of the 20-position methyl ether group by OSi (CH)3)3(ii) a The temperature of the halogenation reaction is 25-30 ℃, and the temperature of the hydrolysis reaction is 0-5 ℃. The yield was 94% and the purity was 97%.
Example 6
Practice ofExample 6 essentially the same as example 3, except that the starting compound, which differs from compound ic in that the hydroxy group at position 17 is replaced by OCOCH3And the carbonyl at position 11 is replaced by a hydroxyl group. The yield was 89% and the purity was 96%.
Example 7
Example 7 is substantially the same as example 1 except that the NCS is replaced with an equal mass amount of NIS. The drying temperature is not more than 30 ℃, the yield is 91 percent, and the purity is 92 percent.
Example 8
Example 8 is substantially the same as example 1 except that triethylamine and NCS were added in amounts equivalent to the amount of the compound ia, and NCS was added in an amount 4 times the amount of the compound ia. The yield is 96 percent, and the purity is 98 percent.
Comparative example 1
Comparative example 1 is essentially the same as example 1 except that the starting compound, which differs from compound Ia in that the 6-position is Br. The yield was 56% and the purity 88%.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (6)
1. A process for the preparation of a 21-halogenated steroid comprising the steps of:
taking a compound shown in a formula I as a raw material, firstly carrying out 21-site halogenation reaction with a halogenating reagent in a mixed solvent of an organic solvent and water, and then carrying out hydrolysis reaction under an acidic condition to obtain a 21-halogenated steroid compound shown in a formula II;
the halogenating reagent is selected from at least one of bromosuccinimide, chlorosuccinimide, iodosuccinimide, dibromohydantoin, dichlorohydantoin, hypochlorous acid, sodium hypochlorite, hypobromous acid and sodium hypobromoate; the halogenation reaction is carried out for 1-4 h at-10-30 ℃ in the presence of an alkaline stabilizer;
the hydrolysis reaction is carried out for 1-2 h at 25-30 ℃; the pH value of the acidic condition of the hydrolysis reaction is 1-2;
further comprising the step of purifying the 21-halogenated steroid: adding alkali into the reaction liquid after the hydrolysis reaction to adjust the pH value to be neutral, concentrating a solvent, adding water, cooling to 0-10 ℃, stirring for 1-2 h, crystallizing, filtering, and washing with water;
the structural formulas of the compound of formula I and the 21-halogenated steroid of formula II are respectively as follows:
wherein the dotted line position represents a single bond or a double bond;
R1is carbonyl or OH;
R2is H, CH3Cl or F;
R3is H, F, Cl, OH or no radical, R4Is carbonyl, OH or H; or, R3And R4Is an epoxy group;
R5is H, α -CH3Or β -CH3；
R6Is H, Si (CH)3)3、COCH3、COCH2CH3；
R7Is Si (CH)3)3、COCH3、COCH2CH3、CH3Or CH2CH3；
X is halogen.
2. The process for the preparation of 21-halogenated steroids according to claim 1, wherein the temperature of the halogenation reaction is between 0 ℃ and 5 ℃.
3. The method of preparing a 21-halogenated steroid according to claim 2, wherein the basic stabilizer is at least one selected from the group consisting of triethylamine, pyridine, sodium carbonate and sodium hydroxide.
4. The method of claim 3, wherein the ratio of the amount of the basic stabilizer to the amount of the compound of formula I is 0.1 to 1: 1.
5. The method of claim 1, wherein the ratio of the amount of said halo reagent to said compound of formula i is 1 to 4: 1.
6. The process for the preparation of 21-halogenated steroids as claimed in claim 5, characterized in that said halogenating agent is chlorosuccinimide and the ratio of the amount of said halogenating agent to that of said compound of formula I is 1.2: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810060392.9A CN108070013B (en) | 2018-01-22 | 2018-01-22 | Process for the preparation of 21-halogenated steroids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810060392.9A CN108070013B (en) | 2018-01-22 | 2018-01-22 | Process for the preparation of 21-halogenated steroids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108070013A CN108070013A (en) | 2018-05-25 |
| CN108070013B true CN108070013B (en) | 2020-05-05 |
Family
ID=62156635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810060392.9A Active CN108070013B (en) | 2018-01-22 | 2018-01-22 | Process for the preparation of 21-halogenated steroids |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108070013B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369762B (en) * | 2018-10-31 | 2021-06-18 | 湖南玉新药业有限公司 | Process for the preparation of 17-carboxylic acid steroids |
| CN112341510B (en) * | 2020-11-12 | 2022-06-24 | 湖南新合新生物医药有限公司 | Preparation method of betamethasone |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772468A (en) * | 2012-10-19 | 2014-05-07 | 华润紫竹药业有限公司 | Preparation methods and purposes of Proellex(R)-V and intermediate of Proellex(R)-V |
-
2018
- 2018-01-22 CN CN201810060392.9A patent/CN108070013B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772468A (en) * | 2012-10-19 | 2014-05-07 | 华润紫竹药业有限公司 | Preparation methods and purposes of Proellex(R)-V and intermediate of Proellex(R)-V |
Non-Patent Citations (2)
| Title |
|---|
| Optical Rotatory Dispersion Studies. XXIII.1 -Haloketones(Part 3);Carl Djerassi et al.;《Journal of the American Chemical Society》;19590520;第81卷;第2383-2386页 * |
| Steroids. LXXXVIII. A new synthesis of deoxycorticosterone acetate and of 16-dehydrodeoxycorticosterone acetate;J. Romo, G. Rosenkranz et al.;《Journal of the American Chemical Society》;19570920;第79卷;第5034-5036页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108070013A (en) | 2018-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108070013B (en) | Process for the preparation of 21-halogenated steroids | |
| CN110698528B (en) | Methylprednisolone intermediate debrominated substance and preparation method thereof | |
| US11618766B2 (en) | Method for preparing 16Alpha-hydroxyprednisolone | |
| BRPI0619428B1 (en) | process for the synthesis of 17a-cyanomethyl-17ß-hydroxystra-4,9-diene-3-one | |
| EP1301526B1 (en) | Oxidation process for preparing the intermediate 6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-androst-1,4-dien-3-one 17.beta.-carboxylic acid | |
| US3965128A (en) | 6β,7β-Epoxy-1α,2α-methylen-D-homo-4-pregnen-3,20-diones | |
| KR20050028907A (en) | C-17 spirolactonization and 6,7 oxidation of steroids | |
| US2599481A (en) | Reduction of steroid epoxides | |
| US2874154A (en) | Process for the production of 20-keto-21-iodo steroids | |
| CN110563787A (en) | preparation method of 5 alpha-androstane-17-hydroxy-3-ketone | |
| CN110790804B (en) | Synthesis method of steroid cortin 21-hydroxyl side chain | |
| US3876633A (en) | Processes and intermediates for 16-substituted corticoid synthesis | |
| US3900467A (en) | Process for the manufacture of ' 13-oxo-7' -acetylthio-17 ' hydroxy 4-androstene-17' yl)-propionic acid' -lactone | |
| CN109369762B (en) | Process for the preparation of 17-carboxylic acid steroids | |
| US2777843A (en) | Preparation of 4-pregnen-17alpha-ol-3, 20-dione | |
| JPS61129197A (en) | Manufacture of pregnane derivative and ester of novel androstane derivative | |
| CN107814824B (en) | Preparation method of tetraene acetate | |
| US3047566A (en) | 6a, 6a-dihalo-6, 7-methylene steroids and method | |
| US3032565A (en) | Process for the manufacture of 6-alkoxy-and 6-keto steroids and compounds obtained thereby | |
| US3684674A (en) | Process for preparing 18-cyano-pregnane compounds | |
| US2666067A (en) | Simultaneous oxidation and halogenation of steroids | |
| US3387006A (en) | 17beta-fluoroalkoxy-3-ketoestrenes | |
| US2567268A (en) | Hydrolysis of steroid sulfates | |
| CN109942659B (en) | Synthetic method of betamethasone intermediate | |
| CN113512085A (en) | Preparation method of mometasone furoate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation Method of 21 Halogenated Steroid Compounds Effective date of registration: 20230613 Granted publication date: 20200505 Pledgee: Hunan Bank Co.,Ltd. Jinshi Branch Pledgor: HUNAN XINHEXIN BIOLOGICAL MEDICINE Co.,Ltd. Registration number: Y2023980043801 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230905 Granted publication date: 20200505 Pledgee: Hunan Bank Co.,Ltd. Jinshi Branch Pledgor: HUNAN XINHEXIN BIOLOGICAL MEDICINE Co.,Ltd. Registration number: Y2023980043801 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |