CN110862430A - Preparation method of 5 α -androstane-3, 17-dione - Google Patents
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Abstract
The invention discloses a preparation method of 5 α -androstane-3, 17-dione, which comprises the following steps of taking 4-androstenedione as a raw material, and preparing a compound 5 α -androstane-3, 17-dione through 17-position keto-hydrocyanation, 3-position keto-ketal, 17-cyanohydrin hydrolysis, 5,6 double bond catalytic hydrogenation and 3-position ketal acid hydrolysis.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of 5 α -androstane-3, 17-dione.
Background
5 α -androstane-3, 17-dione, formula C19H28O2Molecular weight 288.42, having the formula:
5 α -androstane-3, 17-dione is a key intermediate for producing several ten steroid hormone drugs such as androsterone, merlonone, kanglong, mesterone, fravista, and stanozolol, and has wide market application.
The prior art takes diosgenin as a raw material, and obtains diene through reactions such as ring opening, acylation, oxidation, hydrolysis, elimination and the like, diene is subjected to reactions such as oximation, Beckmann rearrangement, acid hydrolysis, alkaline hydrolysis and the like to obtain dehydroepiandrosterone, then obtains epiandrosterone through catalytic hydrogenation reaction, and then prepares a target product through oxidation reaction6+And Cr3+Wherein Cr is6+Is a highly toxic substance, and can cause cancer once ingested into the body to a certain amount. The chromium ions are harmful to the environment and bring great environmental protection pressure to enterprise production.
Chinese patent CN105017362A adopts hypochlorite as an oxidant and 2,2,6, 6-tetramethylpiperidine-nitrogen-oxide (TEMPO) and bromide salt as catalysts to oxidize epiandrosterone into 5 α -androstane-3, 17-dione, although the method has the advantages of avoiding the use of chromic anhydride and mild reaction conditions, the disadvantages are obvious that firstly the price of the epiandrosterone is high and the supply capacity is insufficient, the route for preparing 5 α -androstane-3, 17-dione from epiandrosterone has no cost advantage, secondly the expensive TEMPO is difficult to recover and recycle, then the steroid compound usually has hydrophobicity and needs to be dissolved in an organic solvent with stronger fat solubility, and the hypochlorite and bromide salt are insoluble in the organic solvent with stronger fat solubility, so the smooth proceeding of the oxidation reaction is influenced by the solubility difference.
The domestic sterol biological fermentation method for preparing 4-androstenedione (4 AD for short) has a plurality of production enterprises, and the raw material supply is sufficient. 4AD which is cheap and easily available is used as a key intermediate of steroid hormone medicaments and has extremely wide application. CN103755760A adopts 4AD as a substitute raw material, and is prepared by the steps of metal borohydride reduction, catalytic hydrogenation, chromic anhydride oxidation and the like, and the synthetic route is as follows:
the 4-androstenedione obtained by microbial fermentation of sterol is prepared by the process route, so that the cost advantage is high, the process route is simple, the supply of the 4-androstenedione serving as the raw material is sufficient, but a large amount of chromium-containing wastewater which is difficult to treat is generated by a chromic anhydride oxidation process adopted in an oxidation process, and the burden of environmental protection treatment of enterprises is increased.
The applicant of the present invention has found, according to the patented process, that the HPLC purity of 5 α -androstane-3, 17-diol as a main product in a hydrogenated product obtained in a catalytic hydrogenation step is only 80% or more, that the hydrogenated product contains 15% or more of a main impurity, and that 5 α -androstane-3, 17-diol has a similar polarity to the impurity, and that even after a plurality of solvent refining treatments, the hydrogenated product contains about 5% of the impurity, and that the yield in the catalytic hydrogenation step is greatly reduced to about 60% by the plurality of solvent refining treatments.
The 4-androstene-3, 17-diol (reductant) hydrogenation product contains 5 β -androstane-3, 17-diol in the impurity content of more than 15%, 4-androstene-3, 17-diol is a 3-substituted-4-sterene compound, the 4-sterene structure and the existence of 19-angle methyl group of the compound make the α -face steric hindrance of the compound molecule plane larger, the structure is characterized in that the double bond is close to the catalyst surface from α -face to make a barrier, so that the 3-substituted-4-sterene compound can simultaneously generate two hydrogenation products of 5 α and 5 β during the catalytic hydrogenation,
in order to realize the purpose of preparing a 5 α hydrogenation product by selective catalytic hydrogenation, the applicant of the invention respectively uses palladium carbon and palladium/calcium carbonate as hydrogenation catalysts, uses methanol, ethanol, isopropanol and the like as hydrogenation reaction solvents, and uses a caustic soda flake aqueous solution and hydrochloric acid to regulate and control the pH value (the pH value range is 3.0-9.0) of a reaction system to carry out catalytic hydrogenation reactions of experimental batches with different factors and levels, so that the purpose of improving the purity of the 5 α hydrogenation product cannot be realized, the maximum impurity content in the hydrogenation product obtained from the experimental batches is still above 12%, the generation of isomer hydrogenation byproducts cannot be effectively avoided, and the steroid compound with a 5 β -H structure has almost no hormone activity.
If the 5 β -androstane-3, 17-diol by-product is not removed by refining, but is directly subjected to the next chromic anhydride oxidation reaction along with 5 α -androstane-3, 17-diol, 5 β -androstane-3, 17-dione by-product is concomitantly produced in the synthesis process of 5 α -androstane-3, 17-dione, and since 5 β -androstane-3, 17-dione has more similar polarity to the target product 5 α -androstane-3, 17-dione, purification by refining is more difficult.
Disclosure of Invention
The invention provides a preparation method of 5 α -androstane-3, 17-dione, which aims to solve the problems in the background art.
The invention provides a preparation method of 5 α -androstane-3, 17-dione, which comprises the following steps:
step 1, carrying out hydroxyl cyanation reaction on 4-androstenedione and acetone cyanohydrin in the presence of an organic solvent and organic amine to prepare a compound 17 α -hydroxy-17 β -cyano-androst-4-ene-3-one;
step 2, performing ketal reaction on 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone and ethylene glycol in the presence of chlorinated alkane organic solvent, dehydrating agent triethyl orthoformate and ketal catalyst to obtain a compound 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal;
step 3, carrying out alkaline hydrolysis reaction on 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal in the presence of an alcohol organic solvent and an aqueous solution of alkali to prepare a compound 5-androstene-3-ethylene glycol ketal-17-ketone;
step 4, dropwise adding an alkaline alcoholic solution into the 5-androstene-3-ethylene glycol ketal-17-ketone in an alcohol solvent to adjust the pH value of the system, then carrying out catalytic hydrogenation reaction under the action of a palladium-carbon catalyst, and filtering out the catalyst after the reaction is finished to obtain a solution of a compound 5 α -androstane-3-ethylene glycol ketal-17-ketone;
step 5, performing acid hydrolysis reaction on the solution of 5 α -androstane-3-ethylene glycol ketal-17-ketone and acid, removing the solvent after the acid hydrolysis reaction is finished, filtering, washing with water, and drying to obtain 5 α -androstane-3, 17-dione, wherein the HPLC purity of the 5-androstane-3-ethylene glycol ketal-17-dione is more than 99.0%;
the specific reaction formula is as follows:
preferably, in the reaction step 1, the organic solvent is ethyl acetate, and the organic amine is triethylamine or diethylamine.
Preferably, in the reaction step 2, the chlorinated alkane organic solvent is dichloromethane or chloroform, and the ketal catalyst is p-toluenesulfonic acid or sulfosalicylic acid.
Preferably, in the reaction step 3, the alcohol organic solvent in the alkaline hydrolysis reaction is methanol or ethanol, and the alkali in the alkaline hydrolysis reaction is sodium hydroxide or potassium hydroxide.
Preferably, in the reaction step 4, the alcohol solvent in the catalytic hydrogenation reaction is methanol or ethanol.
Preferably, in the reaction step 4, the acid in the acid hydrolysis reaction is refined hydrochloric acid with a mass percentage concentration of not less than 35% or a sulfuric acid aqueous solution with a mass percentage concentration of not less than 10%.
Preferably, the temperature of the cyanohydrin reaction in the step 1 is 55-65 ℃; and 4-androstenedione: acetone cyanohydrin: organic solvent: the proportion of organic amine is 1W: 0.9V-1.2V: 1.8V-2.2V: 0.15V to 0.3V;
preferably, the ketal reaction temperature in the step 2 is 25-40 ℃, and the ratio of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-one, organic solvent, ethylene glycol, triethyl orthoformate and ketal catalyst is 1W: 1.0V-2.0V: 0.9V-2.0V: 0.4V-1.0V: 0.02W-0.04W;
preferably, the alkaline hydrolysis temperature in the step 3 is 45-60 ℃, and the ratio of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal to alcohol organic solvent to alkali is 1W: 10V-15V: 0.35W-0.45W;
preferably, the catalytic hydrogenation reaction temperature in the step 4 is 20-45 ℃, and the acid hydrolysis reaction temperature is 30-50 ℃; and 5-androstene-3-ethylene ketal-17-one: alcohol solvent: palladium-carbon catalyst: the acid proportion is 1W: 20V to 25V: 0.1W-0.3W: 0.5W-0.8W.
The preparation method of 5 α -androstane-3, 17-dione provided by the invention has the beneficial effects that:
1. the 4-androstenedione with a 4-sterene structure is converted into 5-androstene-3-ethylene glycol ketal-17 ketone (ketal) with a 5-sterene structure before the catalytic hydrogenation reaction is carried out, the conversion of the substrate structure of the catalytic hydrogenation and the proper pH value in the catalytic hydrogenation reaction are beneficial to improving the purity of the hydrogenation product of the catalytic hydrogenation procedure 5 α, and the generation of the hydrogenation product of 5 β is effectively avoided or reduced;
2. in the catalytic hydrogenation reaction and the ketal-removed acid hydrolysis reaction, a combined process is adopted, the catalytic hydrogenation reaction is firstly carried out in an alcohol solvent under the alkalescent condition, after the catalytic hydrogenation reaction is completed, the alcohol solution of the 5 α -androstane-3-ethylene glycol ketal-17-ketone obtained by filtering and removing the palladium-carbon catalyst is directly subjected to the ketal-removed hydrolysis reaction with acid without discharging and separating, so that the yield level of the process route is effectively ensured;
3. the process route of the invention does not need Jones oxidation reaction, and does not produce a large amount of Cr6+And Cr3+The industrial wastewater of (5) and simultaneously avoids the high cost pressure of the hypochlorite oxidation method using expensive TEMPO reagent to the preparation of 5 α -androstane-3, 17-dione;
4. the raw material 4-androstenedione is cheap and easy to obtain, the total mass yield of the new process reaches over 78%, and the product purity can reach over 99.0%, which is higher than the standard of the purity (98.0%) in the prior art.
Detailed Description
The present invention is further described below with reference to specific examples, which are intended to help understanding the technical means of the present invention. It is to be understood that these embodiments are merely illustrative and that the present invention is not limited thereto. The common specification of the palladium-carbon catalyst is 1-5% according to the effective content, the specification of the palladium-carbon catalyst adopted in the embodiment of the invention is 2%, and if other specifications are selected, the dosage can be converted according to the effective content.
Example 1
1. The preparation method of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone comprises the following steps:
adding 4-androstenedione 100g, acetone cyanohydrin 100ml, ethyl acetate 200ml and triethylamine 20ml into a reaction bottle, stirring uniformly, keeping the temperature at 60-65 ℃ for 20 hours for reaction, after the reaction is finished, evaporating all solvents to dryness under reduced pressure, adding methanol for entrainment, concentrating under reduced pressure to be pasty, cooling to below 5 ℃, filtering and drying to obtain 106g of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone, wherein the weight yield is 106%.
2. The preparation method of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal is as follows:
adding 20g of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-one, 0.6g of p-toluenesulfonic acid, 10ml of triethyl orthoformate, 20ml of ethylene glycol and 30ml of dichloromethane into a reaction bottle, uniformly stirring, preserving heat at 33-37 ℃ for 24 hours for reaction, cooling to below 5 ℃ after the reaction is finished, adding 1ml of triethylamine, continuously stirring for 30 minutes, evaporating the solvent under reduced pressure, adding methanol twice, adding 1000ml of water for water separation, filtering, washing with water to be neutral, and drying to obtain 21.6g of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal with the weight yield of 108%.
3. The preparation method of the 5-androstene-3-ethylene ketal-17-ketone comprises the following specific steps:
adding 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal 21.6g and methanol 216ml into a reaction bottle, stirring at room temperature for 30 minutes, dropwise adding sodium hydroxide aqueous solution (9g of sodium hydroxide is dissolved in 30ml of water) into the solvent, heating to 50-55 ℃, keeping the temperature for reaction for 3 hours, after the reaction is finished, concentrating under reduced pressure to paste, adding 1000ml of water for elutriation, filtering, washing with water to be neutral, and drying to obtain 5-androstene-3-ethylene glycol ketal-17-ketone 18.8g, wherein the weight yield is 87.04%.
4. The preparation method of 5 α -androstane-3, 17-dione comprises the following steps:
adding 17.8g of 5-androstene-3-ethylene glycol ketal-17-one and 400ml of ethanol into a reaction bottle, uniformly stirring, dropwise adding an ethanol solution of potassium hydroxide to adjust the pH value to 8.0-8.5, adding 4g of palladium carbon with 2% palladium content, completely replacing air in the reaction bottle with hydrogen, introducing hydrogen at 25-30 ℃ for reacting for 6 hours, completely replacing hydrogen in the reaction bottle with nitrogen after the reaction is finished, and filtering to obtain a 5 α -androstane-3-ethylene glycol ketal-17-one solution;
adding 8.9g of refined hydrochloric acid with the mass percentage concentration of more than or equal to 35.0 percent into a solution of 5 α -androstane-3-ethylene glycol ketal-17-ketone under stirring at room temperature, reacting for 3 hours at 45-50 ℃, cooling to below 5 ℃ after the reaction is finished, dropwise adding a sodium hydroxide aqueous solution with the mass percentage concentration of 5 percent to adjust the pH value to 6.0-7.0, reducing the pressure to evaporate ethanol, cooling to below 5 ℃, slowly adding 500ml of pure water, continuously cooling to below 5 ℃, stirring for 30 minutes, standing for more than 2 hours, filtering, washing with water, and drying to obtain 14.0g of 5 α -androstane-3, 17-dione, wherein the weight yield is 78.6%, and the HPLC purity is 99.3%.
Example 2
1. The preparation method of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone comprises the following steps:
adding 4-androstenedione 100g, acetone cyanohydrin 90ml, ethyl acetate 220ml and diethylamine 15ml into a reaction bottle, stirring uniformly, keeping the temperature at 60-65 ℃ for 24 hours to react, after the reaction is finished, evaporating all solvents under reduced pressure, adding methanol to carry out entrainment, concentrating under reduced pressure to be pasty, cooling to below 5 ℃, filtering and drying to obtain 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone 105.9g with the weight yield of 105.9%.
2. The preparation method of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal is as follows
Adding 20g of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-one, 0.4g of sulfosalicylic acid, 8ml of triethyl orthoformate, 40ml of ethylene glycol and 20ml of dichloromethane into a reaction bottle, uniformly stirring, preserving heat at 25-35 ℃ for 28 hours for reaction, cooling to below 5 ℃ after the reaction is finished, adding 1ml of triethylamine, continuously stirring for 30 minutes, evaporating the solvent under reduced pressure, adding methanol twice, adding 1000ml of water for water separation, filtering, washing with water to be neutral, and drying to obtain 21.8g of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal with the weight yield of 109%.
3. The preparation method of the 5-androstene-3-ethylene ketal-17-ketone comprises the following specific steps:
adding 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal 21.8g and ethanol 327ml into a reaction bottle, stirring at room temperature for 30 minutes, dropwise adding sodium hydroxide aqueous solution (9.8g of sodium hydroxide is dissolved in water 30 ml) into the solvent, heating to 55-60 ℃, keeping the temperature for reaction for 5 hours, after the reaction is finished, concentrating under reduced pressure to paste, adding water 1000ml of water for water precipitation, filtering, washing with water to be neutral, and drying to obtain 5-androstene-3-ethylene glycol ketal-17-ketone 19g, wherein the weight yield is 87.16%.
4. The preparation method of 5 α -androstane-3, 17-dione comprises the following steps:
adding 18g of 5-androstene-3-ethylene glycol ketal-17-one and 450ml of methanol into a reaction bottle, uniformly stirring, dropwise adding an ethanol solution of potassium hydroxide to adjust the pH value to 8.0-8.5, adding 5.4g of palladium carbon with 2% palladium content, completely replacing air in the reaction bottle with hydrogen, introducing hydrogen at 20-25 ℃ for reacting for 5 hours, completely replacing hydrogen in the reaction bottle with nitrogen after the reaction is finished, and filtering to obtain a 5 α -androstane-3-ethylene glycol ketal-17-one solution;
adding 14.4g of sulfuric acid aqueous solution with the mass percentage concentration of more than or equal to 10 percent into a solution of 5 α -androstane-3-ethylene glycol ketal-17-ketone under stirring at room temperature, reacting at 40-45 ℃ for 3.5 hours, cooling to below 5 ℃ after the reaction is finished, dropwise adding sodium hydroxide aqueous solution with the mass percentage concentration of 5 percent to adjust the pH value to 6.0-7.0, reducing the pressure to evaporate methanol, cooling to below 5 ℃, slowly adding 500ml of pure water, continuously cooling to below 5 ℃, stirring for 30 minutes, standing for more than 2 hours, filtering, washing with water, and drying to obtain 14.2g of 5 α -androstane-3, 17-dione, wherein the weight yield is 78.9%, and the HPLC purity is 99.4%.
Example 3
1. The preparation method of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone comprises the following steps:
adding 4-androstenedione 100g, acetone cyanohydrin 120ml, ethyl acetate 180ml and diethylamine 30ml into a reaction bottle, stirring uniformly, keeping the temperature at 55-60 ℃ for 22 hours for reaction, after the reaction is finished, evaporating all solvents under reduced pressure, adding methanol for entrainment, concentrating under reduced pressure to be pasty, cooling to below 5 ℃, filtering and drying to obtain 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone 106.5g with the weight yield of 106.5%.
2. The preparation method of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal is as follows:
adding 20g of 17 α -hydroxy-17 β -cyano-androst-4-ene-3-one, 0.8g of p-toluenesulfonic acid, 20ml of triethyl orthoformate, 18ml of ethylene glycol and 40ml of trichloromethane into a reaction bottle, uniformly stirring, preserving heat at 35-40 ℃ for 22 hours for reaction, cooling to below 5 ℃ after the reaction is finished, adding 1ml of triethylamine, continuously stirring for 30 minutes, evaporating the solvent under reduced pressure, adding methanol for twice, adding 1000ml of water for water separation, filtering, washing with water to be neutral, and drying to obtain 21.4g of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal with the weight yield of 107%.
3. The preparation method of the 5-androstene-3-ethylene ketal-17-ketone comprises the following specific steps:
adding 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal 21.4g and methanol 214ml into a reaction bottle, stirring at room temperature for 30 minutes, dropwise adding a potassium hydroxide aqueous solution (7.49g of potassium hydroxide is dissolved in 30ml of water) into the solvent, heating to 50-55 ℃, keeping the temperature for reaction for 4 hours, after the reaction is finished, concentrating under reduced pressure to paste, adding 1000ml of water for water precipitation, filtering, washing with water to be neutral, and drying to obtain 5-androstene-3-ethylene glycol ketal-17-ketone 18.7g, wherein the weight yield is 86.18%.
4. The preparation method of 5 α -androstane-3, 17-dione comprises the following steps:
adding 17.7g of 5-androstene-3-ethylene glycol ketal-17-one and 354ml of ethanol into a reaction bottle, uniformly stirring, dropwise adding an ethanol solution of potassium hydroxide to adjust the pH value to 8.0-8.5, adding 1.8g of palladium-carbon with 2% palladium content, completely replacing air in the reaction bottle by using hydrogen, introducing hydrogen at 40-45 ℃ for reacting for 8 hours, completely replacing the hydrogen in the reaction bottle by using nitrogen after the reaction is finished, and filtering to obtain a 5 α -androstane-3-ethylene glycol ketal-17-one solution;
adding 10.6g of refined hydrochloric acid with the mass percentage concentration of more than or equal to 35.0 percent into a solution of 5 α -androstane-3-ethylene glycol ketal-17-ketone under stirring at room temperature, reacting for 5 hours at 30-35 ℃, cooling to below 5 ℃ after the reaction is finished, dropwise adding a sodium hydroxide aqueous solution with the mass percentage concentration of 5 percent to adjust the pH value to 6.0-7.0, reducing the pressure to evaporate ethanol, cooling to below 5 ℃, slowly adding 500ml of pure water, continuously cooling to below 5 ℃, stirring for 30 minutes, standing for more than 2 hours, filtering, washing with water, and drying to obtain 14.1g of 5 α -androstane-3, 17-dione, wherein the weight yield is 79.7%, and the HPLC purity is 99.1%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. A preparation method of 5 α -androstane-3, 17-dione, which is characterized by comprising the following steps:
step 1, carrying out hydroxyl cyanation reaction on 4-androstenedione and acetone cyanohydrin in the presence of an organic solvent and organic amine to prepare a compound 17 α -hydroxy-17 β -cyano-androst-4-ene-3-one;
step 2, performing ketal reaction on 17 α -hydroxy-17 β -cyano-androst-4-ene-3-ketone and ethylene glycol in the presence of chlorinated alkane organic solvent, dehydrating agent triethyl orthoformate and ketal catalyst to obtain a compound 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal;
step 3, carrying out alkaline hydrolysis reaction on 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal in the presence of an alcohol organic solvent and an aqueous solution of alkali to prepare a compound 5-androstene-3-ethylene glycol ketal-17-ketone;
step 4, dropwise adding an alkaline alcoholic solution into the 5-androstene-3-ethylene glycol ketal-17-ketone in an alcohol solvent to adjust the pH value of the system, then carrying out catalytic hydrogenation reaction under the action of a palladium-carbon catalyst, and filtering out the catalyst after the reaction is finished to obtain a solution of a compound 5 α -androstane-3-ethylene glycol ketal-17-ketone;
step 5, performing acid hydrolysis reaction on the solution of 5 α -androstane-3-ethylene glycol ketal-17-ketone and acid, removing the solvent after the acid hydrolysis reaction is finished, filtering, washing with water, and drying to obtain 5 α -androstane-3, 17-dione, wherein the HPLC purity of the 5-androstane-3-ethylene glycol ketal-17-dione is more than 99.0%;
the specific reaction formula is as follows:
2. the method of claim 1, wherein in step 1, the organic solvent is ethyl acetate and the organic amine is triethylamine or diethylamine.
3. The method according to claim 1, wherein in the step 2, the chlorinated alkane organic solvent is dichloromethane or chloroform, and the ketal catalyst is p-toluenesulfonic acid or sulfosalicylic acid.
4. The method of claim 1, wherein in step 3, the organic alcohol solvent is methanol or ethanol, and the alkali is sodium hydroxide or potassium hydroxide.
5. The process of claim 1, wherein in step 4, the alcohol solvent used in the catalytic hydrogenation reaction is methanol or ethanol.
6. The process for producing 5 α -androstane-3, 17-dione as claimed in claim 1, wherein in the reaction step 4, the acid in the acid hydrolysis is a purified hydrochloric acid having a concentration of 35% by mass or more or an aqueous sulfuric acid solution having a concentration of 10% by mass or more.
7. The method for preparing 5 α -androstane-3, 17-dione as claimed in claim 1, wherein the temperature of the hydrocyanation reaction in step 1 is 55-65 ℃, and the ratio of 4-androstenedione, acetone cyanohydrin, organic solvent and organic amine is 1W: 0.9V-1.2V: 1.8V-2.2V: 0.15V-0.3V;
8. the method for preparing 5 α -androstane-3, 17-dione as claimed in claim 1, wherein the ketal reaction temperature in step 2 is 25-40 ℃, and the ratio of 17 α -hydroxy-17 β -cyano-androst-4-en-3-one, organic solvent, ethylene glycol, triethyl orthoformate, and ketal catalyst is 1W: 1.0V-2.0V: 0.9V-2.0V: 0.4V-1.0V: 0.02W-0.04W;
9. the method for preparing 5 α -androstane-3, 17-dione as claimed in claim 1, wherein the temperature of alkaline hydrolysis in step 3 is 45-60 ℃, and the ratio of 17 α -hydroxy-17 β -cyano-5-androstene-3-ethylene glycol ketal, alcohol organic solvent, and alkali is 1W: 10V-15V: 0.35W-0.45W;
10. the method for preparing 5 α -androstane-3, 17-dione as claimed in claim 1, wherein the catalytic hydrogenation reaction temperature in step 4 is 20-45 ℃, the acid hydrolysis reaction temperature is 30-50 ℃, and the ratio of 5-androstene-3-ethylene glycol ketal-17-one, alcohol solvent, palladium-charcoal catalyst and acid is 1W: 20V-25V: 0.1W-0.3W: 0.5W-0.8W.
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| CN111995650A (en) * | 2020-07-27 | 2020-11-27 | 浙江神洲药业有限公司 | Synthesis method of alkyl acid testosterone |
| CN111995650B (en) * | 2020-07-27 | 2023-06-27 | 浙江神洲药业有限公司 | Synthesis method of testosterone alkyl acid |
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