阅读说明：本技术 一种5α-雄甾烷-3,17-二酮的制备方法 (Preparation method of 5 α -androstane-3, 17-dione ) 是由 廖俊 *** 付林 曾建华 朱小涛 魏旭力 田玉林 于 2019-12-06 设计创作，主要内容包括：本发明公开了一种5α-雄甾烷-3,17-二酮的制备方法,包括如下步骤：以4-雄烯二酮为原料,经17位酮基羟氰化、3位酮基缩酮、17位羟氰水解、5,6双键催化氢化、3位缩酮酸水解制备得到化合物5α-雄甾烷-3,17-二酮。本发明方法具有生产成本低、产品纯度高、适合工业化生产的优点。(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.)

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.

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.