CN109776643B - Method for preparing etherified intermediate for alclometasone dipropionate - Google Patents
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Abstract
The invention provides a method for preparing an etherified intermediate for alclometasone dipropionate, which comprises the steps of using 16 a-methyl epihydrocortisone as a raw material, and synthesizing the etherified intermediate for alclometasone dipropionate through four-step reaction of 21-bit propionic acid esterification, 7-bit and 11-bit double oxidation into diketone, 17-bit propionic acid esterification and 3-bit enolization etherification protection. The invention takes 16 a-methyl surface hydrocortisone as a raw material, and synthesizes an etherified intermediate for beclomethasone dipropionate through four-step reaction, and the process has the advantages of short synthetic route, economic and environment-friendly process, simple and convenient production operation, high product yield and the like; the solvent used in the production can be recycled and reused, and the industrial production is easy to implement.
Description
Technical Field
The invention belongs to a preparation process technology of steroid hormone medicaments, and particularly relates to a method for preparing an etherified intermediate for beclomethasone dipropionate.
Background
Alclometasone dipropionate (molecular formula C)28H37ClO7) The chemical name of the compound is 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-diketone-17, 21-dipropionate, the compound is a potent steroid cortical hormone drug, has potent local anti-inflammatory, itching relieving and blood vessel contraction effects, is mainly used for treating eczema, atopic dermatitis, psoriasis and other skin diseases clinically, and has low side effect, good effect and wide market prospect. The traditional production method of alclometasone dipropionate is characterized by using defluorinated dexamethasone acetate as a raw material, and carrying out six-step chemical reactions of DDQ 6-site dehydrogenation, 21-site base catalytic hydrolysis, 17-and 21-site triethyl propionate cycloesterification, acid-catalyzed cyclic ester hydrolysis, 21-site propyl esterification, and addition of 7a-Cl on 6-and 7-site HCl gas to prepare the alclometasone dipropionate, wherein the process route is shown in figure 1. The synthesis method has long synthesis route, the total synthesis yield is only 2.678%, especially the final step of 6-position and 7-position HCl gas addition reaction, the synthesis yield is less than 20%, and the method has the advantages of low total synthesis yield, more side reactions of multi-step synthesis chemical reaction, large amount of generated impurities, difficult refining and purification, more three wastes, difficult treatment and easy environmental pollution, so that the production cost and market price of the alclometasone dipropionate are high, and the medication burden of patients is increased.
Therefore, there is a need in the art for a new method for preparing alclometasone dipropionate.
Disclosure of Invention
The invention provides a method for preparing an etherified intermediate for alclometasone dipropionate.
The technical scheme of the invention is that the method for preparing the etherified intermediate for alclometasone dipropionate comprises the following steps of using 16 a-methyl epihydrocortisone as a raw material, carrying out esterification on 21-bit propionic acid, carrying out dioxygenation on 7-bit and 11-bit to form diketone, carrying out esterification on 17-bit propionic acid, and carrying out enolization etherification protection on 3-bit enolization to synthesize the etherified intermediate for alclometasone dipropionate, and comprises the following specific steps:
A. synthesizing an esterified product, namely taking 16 a-methyl epihydrocortisone as a raw material, and carrying out esterification reaction on the raw material and 21-hydroxy of propionic anhydride in a first organic solvent under the catalysis of an acid catalyst to obtain the esterified product: 16 a-methyl epihydrocortisone-21 propionate;
B. the synthesis of oxide is carried out by carrying out 7, 11-site oxidation reaction on esterified substance and oxidant in acid-containing second organic solvent with 11a hydroxyl and 7-site active hydrogen in molecule to obtain oxide: 16 a-methyl-17 a-hydroxy-21-propionyloxy-pregn-4-ene-3, 7,11, 20-tetraone;
C. the diester is synthesized by the following steps that 17 a-hydroxyl of oxide and propionic anhydride are subjected to esterification reaction in a third organic solvent under the catalysis of an acid catalyst to generate the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone;
D. synthesizing an etherate, namely, carrying out enol etherification protection reaction on the diester and triethyl orthoformate in a fourth organic solvent under the catalysis of an acid catalyst with a ketone group in a 3-keto-4-ene structure in a molecule to obtain the etherate, namely an etherified intermediate for alclometasone dipropionate: 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione.
Further, the method comprises the following specific operation steps:
A. synthesizing an esterified substance: dissolving 16 a-methyl epihydrocortisone in a first organic solvent, adding propionic anhydride at 10-50 ℃, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), adding alkali for neutralization after the reaction is finished, recovering the organic solvent under reduced pressure, crystallizing by using ethanol water solution, and drying to obtain an ester: 16 a-methyl epihydrocortisone-21 propionate, the HPLC content is 97.0-98.5%, and the weight yield is 110-115%;
B. synthesizing an oxide: dissolving the esterified substance into a second organic solvent, slowly dripping an oxidant at 10-50 ℃ within 2-3 hours, keeping the temperature at 10-50 ℃ for continuously reacting for 1-2 hours after dripping, confirming the reaction end point by TLC, adding a proper amount of sodium hydrosulfite to remove excessive oxidant after the reaction is finished, concentrating under reduced pressure to recover 90-95% of the organic solvent, cooling, elutriating, centrifuging, discharging filtrate into a wastewater treatment pool, and drying a filter cake to obtain an oxide, wherein the HPLC content is 95.0-98.5%, and the weight yield is 95-100%;
C. synthesis of diester: dissolving the oxide into a third organic solvent, keeping the temperature at 10-80 ℃, adding propionic anhydride, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), cooling to 25-30 ℃ after the reaction is finished, adding a proper amount of alkali to neutralize until the pH value of the solution is 6.5-7.5, decompressing, concentrating and recovering 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring and crystallizing for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, the HPLC content is 98.0-99.0%, and the weight yield is 110-115%;
D. synthesizing an etherate: dissolving the diester into a fourth organic solvent, adding triethyl orthoformate and an acid catalyst, keeping the temperature at 10-80 ℃ for reaction for 3-4 hours, confirming the reaction end point by TLC, adding a proper amount of alkali to neutralize the pH value of the solution to 6.5-7.5 after the reaction is finished, decompressing, concentrating and recovering 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring and crystallizing for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherified intermediate for alclometasone dipropionate: the 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione has the HPLC content of 97.0-99.0% and the weight yield of 100-105%.
Further, in the specific steps:
A. the first organic solvent in the synthesized esterified product is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst ═ 1 g: 0.3-0.5 g: 0.01-0.15 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent ═ 1 g: 1-5 ml;
B. the second organic solvent in the synthesized oxide is one of toluene, acetone, chloroform, DME, tetrahydrofuran, DMSO, dioxane and glacial acetic acid; the oxidant is one of chromium oxide, PPC and sodium hypohalite; the weight ratio of reactants is as follows: oxidant 1 g: 0.2-0.8 g; the ratio of reactants to solvent is, esterified: second organic solvent ═ 1 g: 3-10 ml;
C. the third organic solvent in the synthesized diester is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst ═ 1 g: 0.3-0.5 g: 0.05-0.25 g; the ratio of the reactants to the solvent is as follows: third organic solvent ═ 1 g: 1-8 ml;
D. the fourth organic solvent in the synthesized etherate is one of toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, DME and lower alcohol with the carbon number below 4; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid and trifluoroacetic acid; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst ═ 1 g: 0.6-1.2 ml: 0.05-0.25 g; the ratio of reactants to solvent is, diester: fourth organic solvent ═ 1 g: 2-8 ml.
Further, in the specific steps:
A. the first organic solvent in the synthetic ester is propionic acid; the reaction temperature is 25-30 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst ═ 1 g: 0.4 g: 0.05 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent ═ 1 g: 2 ml;
B. the second organic solvent in the synthetic oxide is glacial acetic acid; the reaction temperature is 20-25 ℃; the oxidizing agent is chromium oxide; the weight ratio of reactants is as follows: oxidant 1 g: 0.4 g; the ratio of reactants to solvent is, esterified: second organic solvent ═ 1 g: 5ml of the solution;
C. the third organic solvent in the synthesis of the diester is propionic acid; the reaction temperature is 30-35 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst ═ 1 g: 0.4 g: 0.1 g; the ratio of the reactants to the solvent is as follows: third organic solvent ═ 1 g: 3 ml;
D. the fourth organic solvent in the synthesis of the etherate is dichloromethane; the acid catalyst for the reaction is p-toluenesulfonic acid; the reaction temperature is 20-25 ℃; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst ═ 1 g: 0.9 ml: 0.10 g; the ratio of reactants to solvent is, diester: fourth organic solvent ═ 1 g: 6 ml.
Further, in the specific steps:
D. the base for synthesizing the etherified product and neutralizing the acid is one of inorganic base sodium hydroxide, sodium carbonate or organic base pyridine and triethylamine.
Further, in the specific steps:
D. the base for neutralizing the acid in the synthesis of the etherate is triethylamine.
The beneficial effects of the invention include:
the invention takes 16 a-methyl surface hydrocortisone as a raw material, and synthesizes an etherified intermediate for beclometasone dipropionate through four-step reactions such as esterification, oxidation, double esterification, etherification and the like, and the process has the advantages of short synthetic route, economic and environment-friendly process, simple and convenient production operation, high product yield and the like; the solvent used in the production can be recycled and reused, and the industrial production is easy to implement.
Drawings
FIG. 1 is a conventional synthesis route diagram of alclometasone dipropionate.
FIG. 2 is a synthesis route diagram of alclometasone dipropionate according to the present invention.
Detailed Description
In order to explain the gist and spirit of the present invention in more detail, several embodiments are described below.
Example 1
A. Preparation of an esterified substance: adding 100g of 16 a-methyl hydrocortisone, 200ml of propionic acid, 40g of propionic anhydride and 5g of p-toluenesulfonic acid into a 1000ml three-neck flask, reacting at 20-25 ℃ for 6-8 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding the reaction liquid into 5000ml three-neck flask filled with 2000ml of sodium hydroxide solution with the molar concentration of 5%, stirring and crystallizing at 0-5 ℃ for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, adding a filter cake into 600ml of ethanol aqueous solution with the molar concentration of 20%, stirring at 30-35 ℃ for 5-6 hours, cooling to 0-5 ℃ and stirring and crystallizing for 5-6 hours, filtering, applying the filtrate to the next refining process, washing and drying the filter cake to obtain an esterified substance: 112g of 16 a-methyl epihydrocortisone-21 propionate, 97.4 percent of HPLC content and 112 percent of weight yield;
B. preparation of oxides: adding 100g of the esterified substance prepared by the step A and 500ml of glacial acetic acid into a 1000ml three-neck flask, stirring to completely dissolve the esterified substance and the glacial acetic acid, then controlling the temperature to be 20-25 ℃, slowly dropwise adding an oxidant solution prepared from 40g of chromium oxide and 80g of water, completing dropwise addition within about 2.5-3 hours, keeping the temperature at 20-25 ℃ after completing dropwise addition, continuing to react for 1-2 hours, determining a reaction end point by TLC (thin layer chromatography), adding 10g of sodium hydrosulfite after completing the reaction to remove excessive oxidant, then performing reduced pressure concentration to recover about 90% of glacial acetic acid, cooling to 20-30 ℃, adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 3-4 hours, filtering, discharging a filter cake into a wastewater treatment tank, washing and drying to obtain 98g of oxide, wherein the HPLC content is 97.5%, and the weight yield is 98%;
C. preparation of diester: adding 100g of the oxide prepared by the B, 300ml of propionic acid, 40g of propionic anhydride and 10g of p-toluenesulfonic acid into a 1000ml three-necked bottle, keeping the temperature at 30-35 ℃ for reacting for 6-8 hours, confirming the reaction end point by TLC, cooling to 25-30 ℃ after the reaction is finished, slowly dropwise adding the reaction liquid into 5000ml of three-necked bottle filled with 2000ml of sodium hydroxide solution with the molar concentration of 5%, stirring at 0-5 ℃ for crystallizing for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a diester: 113.6g of 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, 98.5 percent of HPLC content and 113.6 percent of weight yield;
D. preparation of etherate: adding 100g of diester prepared by C into a 1000ml three-necked bottle, adding 600ml of dichloromethane, then adding 90ml of triethyl orthoformate and 10g of p-toluenesulfonic acid, keeping the temperature at 20-25 ℃ for reacting for 3-4 hours, confirming the reaction end point by TLC, after the reaction is finished, adding a proper amount of triethylamine to neutralize until the pH of the solution is 6.5-7.5, carrying out reduced pressure concentration to recover 90-95% of dichloromethane, cooling to 20-25 ℃, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 1.5-2.5 hours, filtering, discharging the filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain an etherate: 104g of 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, 97.6 percent of HPLC content and 104 percent of weight yield;
E. preparation of a reduced product: adding 100g of the etherate prepared by the step D and 1200ml of methanol into a 2000ml three-necked bottle, keeping the temperature at 25-30 ℃, stirring to completely dissolve the solid, slowly adding 16g of a sodium borohydride reducing agent, keeping the adding for about 1.5-2.5 hours, then continuing to keep the temperature at 25-30 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 100g of a hydrochloric acid aqueous solution with the molar concentration of 30% to ensure that the pH of the system is 2-3, continuing to perform hydrolysis reaction at 25-30 ℃ for 2-3 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly adding a proper amount of alkali to neutralize the pH of the system to 6-7, then performing reduced pressure concentration to recover 90-95% of organic solvent methanol, cooling, slowly adding 600ml of pure water for elutriation, filtering, discharging the filtrate into a waste water treatment pool, washing and drying a filter cake to obtain a reduced crude product, recrystallizing the crude product by using 500ml of an alcohol aqueous solution with, obtaining a reduced product: 74.2g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, 98.8 percent of HPLC content and 74.2 percent of weight yield;
F. 1-preparation of dehydrogenate: adding 100g of the reduced product prepared by the step E, 1200ml of dioxane and 80g of DDQ (dichloro-diphenyl-hydroquinone) dehydrogenating agent into a 2000ml three-necked bottle, stirring to completely dissolve the reduced product, heating to 75-80 ℃, keeping the temperature for reaction for 6-10 hours, confirming the reaction end point by TLC (thin layer chromatography), filtering out hydroquinone generated in the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy excessive DDQ, then decompressing and concentrating to recover 90-95% of organic solvent dioxane, cooling, slowly adding 600ml of pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a 1-dehydrogenated product crude product, recrystallizing the crude product by using 500ml of aqueous solution containing 20% alcohol and 10% caustic soda to obtain the 1-dehydrogenated product: 63.8g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, 98.2% HPLC content and 63.8% weight yield;
G. preparation of alclometasone dipropionate: adding 100g of the 1-dehydrogenized substance prepared by the F, 800ml of toluene and 200g of pyridine into a 2000ml three-necked bottle, heating and stirring to completely dissolve solids, then adding 80g of phosphorus trichloride chlorinating agent, keeping the temperature at 40-45 ℃, stirring and reacting for 4-6 hours, confirming the reaction end point by TLC, after the reaction is finished, adding 500g of caustic soda solution with the molar concentration of 30% for 2 times to neutralize and wash until the pH value of an aqueous solution layer is 6-7, concentrating under reduced pressure to recover 90-95% of organic solvent toluene, cooling to 20-25 ℃, adding 600ml of pure water, stirring and crystallizing at 0-5 ℃ for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a crude alclometasone dipropionate crude product, refluxing the crude product with 600ml of alcohol and 5g of activated carbon for 1 hour, filtering, decolorizing the filter cake, washing the filtrate, combining the filtrate and a washing solution, concentrating 80% alcohol, and (3) stirring and crystallizing at 0-5 ℃ for 3-4 hours, treating the obtained solid, and adding methanol-acetone-isopropyl ether: 1: 3, recrystallizing the mixed solvent to obtain alclometasone dipropionate: 64.2g of 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-dione-17, 21-dipropionate, mp: the HPLC content is 99.4 percent at the temperature of 214-216 ℃, and the weight yield is 64.2 percent.
Example 2
A. Preparation of an esterified substance: adding 100g of 16 a-methyl hydrocortisone, 500ml of chloroform, 40g of propionic anhydride and 8g of p-toluenesulfonic acid into a 1000ml three-neck flask, reacting at 20-25 ℃ for 6-8 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 20ml of sodium hydroxide solution with the molar concentration of 50%, concentrating under reduced pressure after water separation to recover 90-95% of chloroform, then adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, adding the filter cake into 600ml of ethanol aqueous solution with the molar concentration of 20%, stirring at 30-35 ℃ for 5-6 hours, cooling to 0-5 ℃, stirring and crystallizing for 5-6 hours, filtering, mechanically applying the filtrate to the next refining process, washing and drying the filter cake to obtain an esterified substance: 109.5g of 16 a-methyl-epi-hydrocortisone-21 propionate, 97.8% HPLC content and 109.5% weight yield;
B. preparation of oxides: adding 100g of the esterified substance prepared by the step A and 600ml of acetone into a 1000ml three-necked bottle, stirring to completely dissolve the esterified substance, controlling the temperature to be 20-25 ℃, slowly dropwise adding an oxidant solution prepared from 40g of chromium oxide and 80g of pure water, completing dropwise addition within about 2.5-3 hours, keeping the temperature at 20-25 ℃ after completing dropwise addition, continuing to react for 1-2 hours, confirming the reaction end point by TLC, adding 10g of sodium hydrosulfite after completing the reaction to remove excessive oxidant, then performing reduced pressure concentration to recover about 90% of acetone, cooling to 20-30 ℃, adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 3-4 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying filter cakes to obtain 97.4g of oxides, wherein the HPLC content is 96.6%, and the weight yield is 97.4%;
C. preparation of diester: adding 100g of the oxide prepared by the B, 300ml of chloroform, 40g of propionic anhydride and 10g of p-toluenesulfonic acid into a 1000ml three-necked bottle, keeping the temperature at 50-55 ℃ for reacting for 6-8 hours, confirming the reaction end point by TLC, cooling to 25-30 ℃ after the reaction is finished, slowly dropwise adding the mixture into the reaction solution to 50ml of sodium hydroxide solution with the molar concentration of 30%, removing a water layer, washing once by 50ml of pure water, draining off water, concentrating under reduced pressure to recover 90-95% of chloroform solvent, cooling, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, washing a filter cake with water, and drying to obtain the diester: 112.2g of 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetrone, 97.8 percent of HPLC content and 112.2 percent of weight yield;
D. preparation of etherate: adding 100g of diester prepared by C, 600ml of THF, 90ml of triethyl orthoformate and 10g of concentrated sulfuric acid into a 1000ml three-necked bottle, keeping the temperature at 20-25 ℃ for reacting for 3-4 hours, confirming the reaction end point by TLC, adding a proper amount of sodium carbonate solid to neutralize the pH of the solution to 6.5-7.5 after the reaction is finished, concentrating under reduced pressure to recover 90-95% of THF, cooling to 20-25 ℃, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 1.5-2.5 hours, filtering, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherate: 101.8g of 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, 96.4 percent of HPLC content and 101.8 percent of weight yield;
E. preparation of a reduced product: adding 100g of the etherate prepared by the step D and 1200ml of DME into a 2000ml three-necked bottle, keeping the temperature at 25-30 ℃, stirring to completely dissolve the solid, slowly adding 18g of a sodium borohydride reducing agent, keeping the adding for about 1.5-2.5 hours, then continuing to keep the temperature at 25-30 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 120g of a hydrochloric acid aqueous solution with the molar concentration of 30% to ensure that the PH of the system is 2-3, continuing to perform hydrolysis reaction at 25-30 ℃ for 2-3 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly adding an appropriate amount of alkali to neutralize the PH of the system to 6-7, then performing reduced pressure concentration to recover 90-95% of organic solvent DME, cooling, slowly adding 600ml of pure water for elutriation, filtering, discharging the filtrate into a waste water treatment pool, washing and drying a filter cake to obtain a reduced crude product, recrystallizing the crude product by using 500ml of an alcohol aqueous solution, obtaining a reduced product: 72.6g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, 97.2 percent of HPLC content and 72.6 percent of weight yield;
F. 1-preparation of dehydrogenate: adding 100g of the reduced product prepared by the step E, 1200ml of toluene and 80g of DDQ (dichloro-diphenyl-hydroquinone) dehydrogenating agent into a 2000ml three-necked bottle, stirring to completely dissolve the reduced product, heating to 75-80 ℃, keeping the temperature and reacting for 6-10 hours, confirming the reaction end point by TLC (thin layer chromatography), filtering out hydroquinone generated in the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy excessive DDQ, then decompressing and concentrating to recover 90-95% of organic solvent toluene, cooling, slowly adding 600ml of pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain a 1-dehydrogenated product crude product, recrystallizing the crude product by using 500ml of aqueous solution containing 20% alcohol and 10% of caustic soda to obtain the 1-dehydrogenated product: 61.5g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, 97.8 percent of HPLC content and 61.5 percent of weight yield;
G. preparation of alclometasone dipropionate: adding 100G of the 1-dehydrogenized substance prepared by the F, 800ml of chloroform and 200G of triethylamine into a 2000ml three-necked bottle, heating and stirring to completely dissolve solids, then adding 80G of phosphorus trichloride chlorinating agent, keeping the temperature at 40-45 ℃, stirring and reacting for 4-6 hours, confirming the reaction end point by TLC, after the reaction is finished, adding 500G of caustic soda solution with the molar concentration of 30% for 2 times to neutralize and wash the aqueous solution layer until the pH of the aqueous solution layer is 6-7, concentrating under reduced pressure to recover 90-95% of organic solvent chloroform, cooling to 20-25 ℃, adding 600ml of pure water, stirring and crystallizing at 0-5 ℃ for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a crude alclometasone dipropionate product, and recrystallizing the crude product according to the method G in example 1 to obtain alclometasone dipropionate: 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-dione-17, 21-dipropionate 61.6g, m.p.: 214-215.5 ℃, HPLC content 99.3% and weight yield 61.6%.
Example 3
A. Preparation of an esterified substance: adding 100g of 16 a-methyl hydrocortisone, 500ml of toluene, 40g of propionic anhydride and 6g of trifluoroacetic acid into a 1000ml three-necked bottle, reacting at 20-25 ℃ for 6-8 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 20ml of sodium hydroxide solution with the molar concentration of 50%, concentrating under reduced pressure after water separation to recover 90-95% of toluene, then adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, adding the filter cake into 600ml of ethanol aqueous solution with the molar concentration of 20%, stirring at 30-35 ℃ for 5-6 hours, cooling to 0-5 ℃, stirring and crystallizing for 5-6 hours, filtering, mechanically applying the filtrate to the next refining process, washing and drying the filter cake to obtain an ester: 106.8g of 16 a-methyl-epi-hydrocortisone-21 propionate, 97.2% HPLC content and 106.8% weight yield;
B. preparation of oxides: adding 100g of the esterified substance prepared by the step A and 600ml of chloroform into a 1000ml three-necked bottle, stirring to completely dissolve the esterified substance, then slowly dropwise adding an oxidant solution prepared from 40g of chromium oxide and 80g of pure water at the temperature of 20-25 ℃, completing dropwise adding within 2.5-3 hours, keeping the temperature at 20-25 ℃ after completing dropwise adding, continuing to react for 1-2 hours, confirming the reaction end point by TLC, adding 10g of sodium hydrosulfite after completing the reaction to remove excessive oxidant, then decompressing and concentrating to recover 90% of chloroform, cooling to 20-30 ℃, adding 500ml of pure water, stirring and crystallizing at the temperature of 0-5 ℃ for 3-4 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying filter cakes to obtain 98.2g of oxide, the HPLC content is 97.5%, and the weight yield is 98.2%;
C. preparation of diester: adding 100g of the oxide prepared by the B, 300ml of toluene, 40g of propionic anhydride and 12g of phosphoric acid into a 1000ml three-necked bottle, reacting for 6-8 hours at 50-55 ℃ while keeping the temperature, confirming the reaction end by TLC, cooling to 25-30 ℃ after the reaction is finished, slowly dripping the mixture into a reaction solution until 80ml of a sodium hydroxide solution with the molar concentration of 30%, removing a water layer, washing once by using 50ml of pure water, draining off water, concentrating under reduced pressure to recover 90-95% of solvent toluene, adding 500ml of pure water after cooling, stirring and crystallizing for 4-5 hours at 0-5 ℃, filtering, discharging filtrate into a wastewater treatment tank, washing filter cakes with water, and drying to obtain the diester: 111.8g of 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, 98.2 percent of HPLC content and 111.8 percent of weight yield;
D. preparation of etherate: adding 100g of diester prepared by the C, 600ml of ethanol, 90ml of triethyl orthoformate and 10g of trifluoroacetic acid into a 1000ml three-necked bottle, keeping the temperature at 20-25 ℃ for reacting for 3-4 hours, confirming the reaction end point by TLC, adding an appropriate amount of pyridine solid for neutralizing until the pH of the solution is 6.5-7.5 after the reaction is finished, concentrating under reduced pressure for recovering 90-95% of ethanol, cooling to 20-25 ℃, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherate: 102.6g of 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, 96.8 percent of HPLC content and 102.6 percent of weight yield;
E. preparation of a reduced product: adding 100g of etherate prepared by the step D and 1200ml of THF into a 2000ml three-necked bottle, keeping the temperature at 25-30 ℃, stirring to completely dissolve the solid, slowly adding 18g of potassium borohydride reducing agent, keeping the adding for about 1.5-2.5 hours, then continuing to keep the temperature at 25-30 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 100g of sulfuric acid aqueous solution with the molar concentration of 50% to ensure that the pH of the system is 2-3, continuing to hydrolyze at 25-30 ℃ for 2-3 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly adding a proper amount of alkali to neutralize the pH of the system to 6-7, then decompressing and concentrating to recover 90-95% of organic solvent THF, cooling, slowly adding 600ml of pure water for elutriation, filtering, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain a reduced product, recrystallizing the crude product by using 500ml of alcohol aqueous solution with the molar concentration of 50%, obtaining a reduced product: 70.8g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, 97.6 percent of HPLC content and 70.8 percent of weight yield;
F. 1-preparation of dehydrogenate: adding 100g of the reduced product prepared by the step E, 1200ml of ethyl acetate and 85g of DDQ (dichloro-diphenyl-hydroquinone) dehydrogenating agent into a 2000ml three-necked bottle, stirring to completely dissolve the reduced product, heating to 75-80 ℃, keeping the temperature for reaction for 6-10 hours, confirming the reaction end point by TLC (thin layer chromatography), filtering out hydroquinone generated in the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy excessive DDQ, then decompressing and concentrating to recover 90-95% of organic solvent ethyl acetate, cooling, slowly adding 600ml of pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain a 1-dehydrogenated product crude product, recrystallizing the crude product by using 500ml of aqueous solution containing 20% alcohol and 10% caustic soda to obtain the 1-dehydrogenated product: 62.4g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, 97.2 percent of HPLC content and 62.4 percent of weight yield;
G. preparation of alclometasone dipropionate: adding 100G of the 1-dehydrogenized substance prepared by the F, 800ml of toluene and 200G of pyridine into a 2000ml three-necked bottle, heating and stirring to completely dissolve solids, then adding 80G of thionyl chloride chlorinating agent, keeping the temperature at 40-45 ℃, stirring and reacting for 4-6 hours, confirming the reaction end point by TLC, after the reaction is finished, adding 500G of caustic soda solution with the molar concentration of 30% for 2 times to neutralize and wash the aqueous solution layer PH 6-7, concentrating under reduced pressure to recover 90-95% of organic solvent toluene, cooling to 20-25 ℃, adding 600ml of pure water, stirring and crystallizing at 0-5 ℃ for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain crude alclometasone dipropionate, and recrystallizing the crude product according to the method G in example 1 to obtain alclometasone dipropionate: 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-dione-17, 21-dipropionate 62.8g, m.p.: 214-215.5 ℃, HPLC content of 99.2% and weight yield of 62.8%.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions and substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (6)
1. A method for preparing an etherified intermediate for alclometasone dipropionate is characterized in that the method comprises the following steps of using 16 a-methyl epihydrocortisone as a raw material, carrying out esterification by 21-bit propionic acid, dioxygenation by 7-bit and 11-bit to obtain diketone, esterification by 17-bit propionic acid, and carrying out enolization and etherification protection by 3-bit enolization to synthesize the etherified intermediate for alclometasone dipropionate, and the specific steps comprise:
A. synthesizing an esterified product, namely taking 16 a-methyl epihydrocortisone as a raw material, and carrying out esterification reaction on the raw material and 21-hydroxy of propionic anhydride in a first organic solvent under the catalysis of an acid catalyst to obtain the esterified product: 16 a-methylepihydrocortisone-21-propionate;
B. the synthesis of oxide is carried out by carrying out 7, 11-site oxidation reaction on esterified substance and oxidant in acid-containing second organic solvent with 11a hydroxyl and 7-site active hydrogen in molecule to obtain oxide: 16 a-methyl-17 a-hydroxy-21-propionyloxy-pregn-4-ene-3, 7,11, 20-tetraone; the second organic solvent containing acid is glacial acetic acid, and the oxidant is chromium oxide;
C. the diester is synthesized by the following steps that 17 a-hydroxyl of oxide and propionic anhydride are subjected to esterification reaction in a third organic solvent under the catalysis of an acid catalyst to generate the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone;
D. synthesizing an etherate, namely, carrying out enol etherification protection reaction on the diester and triethyl orthoformate in a fourth organic solvent under the catalysis of an acid catalyst with a ketone group in a 3-keto-4-ene structure in a molecule to obtain the etherate, namely an etherified intermediate for alclometasone dipropionate: 3-ethoxy-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione.
2. The method according to claim 1, characterized in that the method comprises the following specific operating steps:
A. synthesizing an esterified substance: dissolving 16 a-methyl epihydrocortisone in a first organic solvent, adding propionic anhydride at 10-50 ℃, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), adding alkali for neutralization after the reaction is finished, recovering the organic solvent under reduced pressure, crystallizing by using ethanol water solution, and drying to obtain an ester: 16 a-methyl epihydrocortisone-21-propionate, the HPLC content is 97.0-98.5%, and the weight yield is 110-115%;
B. synthesizing an oxide: dissolving the esterified substance into a second organic solvent, slowly dripping an oxidant at 10-50 ℃ within 2-3 hours, keeping the temperature at 10-50 ℃ for continuously reacting for 1-2 hours after dripping, confirming the reaction end point by TLC, adding a proper amount of sodium hydrosulfite to remove excessive oxidant after the reaction is finished, concentrating under reduced pressure to recover 90-95% of the organic solvent, cooling, elutriating, centrifuging, discharging filtrate into a wastewater treatment pool, and drying a filter cake to obtain an oxide, wherein the HPLC content is 95.0-98.5%, and the weight yield is 95-100%;
C. synthesis of diester: dissolving the oxide into a third organic solvent, keeping the temperature at 10-80 ℃, adding propionic anhydride, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), cooling to 25-30 ℃ after the reaction is finished, adding a proper amount of alkali to neutralize until the pH value of the solution is 6.5-7.5, decompressing, concentrating and recovering 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring and crystallizing for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, the HPLC content is 98.0-99.0%, and the weight yield is 110-115%;
D. synthesizing an etherate: dissolving the diester into a fourth organic solvent, adding triethyl orthoformate and an acid catalyst, keeping the temperature at 10-80 ℃ for reaction for 3-4 hours, confirming the reaction end point by TLC, adding a proper amount of alkali to neutralize the pH value of the solution to 6.5-7.5 after the reaction is finished, decompressing, concentrating and recovering 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring and crystallizing for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherified intermediate for alclometasone dipropionate: 3-ethoxy-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, HPLC content 97.0-99.0%, weight yield 100-105%.
3. The method according to claim 1 or 2, characterized in that in said specific steps:
A. the first organic solvent in the synthesized esterified product is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst =1 g: 0.3-0.5 g: 0.01-0.15 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent =1 g: 1-5 ml;
B. the weight ratio of reactants in the synthesized oxide is that esterified substances: oxidant =1 g: 0.2-0.8 g; the ratio of reactants to solvent is, esterified: second organic solvent =1 g: 3-10 ml;
C. the third organic solvent in the synthesized diester is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst =1 g: 0.3-0.5 g: 0.05-0.25 g; the ratio of the reactants to the solvent is as follows: third organic solvent =1 g: 1-8 ml;
D. the fourth organic solvent in the synthesized etherate is one of toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, DME and lower alcohol with the carbon number below 4; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid and trifluoroacetic acid; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst =1 g: 0.6-1.2 ml: 0.05-0.25 g; the ratio of reactants to solvent is, diester: fourth organic solvent =1 g: 2-8 ml.
4. The method according to claim 3, characterized in that in said specific steps:
A. the first organic solvent in the synthetic ester is propionic acid; the reaction temperature is 25-30 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst =1 g: 0.4 g: 0.05 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent =1 g: 2 ml;
B. the reaction temperature in the synthesis of the oxide is 20-25 ℃; the weight ratio of reactants is as follows: oxidant =1 g: 0.4 g; the ratio of reactants to solvent is, esterified: second organic solvent =1 g: 5ml of the solution;
C. the third organic solvent in the synthesis of the diester is propionic acid; the reaction temperature is 30-35 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst =1 g: 0.4 g: 0.1 g; the ratio of the reactants to the solvent is as follows: third organic solvent =1 g: 3 ml;
D. the fourth organic solvent in the synthesis of the etherate is dichloromethane; the acid catalyst for the reaction is p-toluenesulfonic acid; the reaction temperature is 20-25 ℃; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst =1 g: 0.9 ml: 0.10 g; the ratio of reactants to solvent is, diester: fourth organic solvent =1 g: 6 ml.
5. The method according to claim 2, characterized in that in said specific steps:
D. the base for synthesizing the etherified product and neutralizing the acid is one of inorganic base sodium hydroxide, sodium carbonate or organic base pyridine and triethylamine.
6. The method according to claim 5, characterized in that in the specific steps:
D. the base for neutralizing the acid in the synthesis of the etherate is triethylamine.
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