Preparation method of dihydrotestosterone and intermediate thereof

Abstract

The invention discloses a preparation method of dihydrotestosterone and an intermediate thereof, according to the method, epiandrosterone is used as a raw material, the dihydrotestosterone (DHT) is obtained through oxidation, etherification, reduction hydrolysis and refining, and the purity of the obtained DHT is greater than or equal to 99%. The method is simple and convenient to operate, easy to implement and environment-friendly.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a green synthesis method of dihydrotestosterone and its intermediate 5α-androsten-3,17-dione. Background Art

[0002] Dihydrotestosterone (Dihydrotestosterone), the structural formula is as follows: It is a steroid hormone and a metabolite of the natural androgen testosterone, formed through the action of the NADPH-dependent enzyme 5α-reductase. It is involved in a wide range of diseases, such as male pattern baldness, benign prostatic hyperplasia, and prostate cancer. As an anabolic steroid, DHT is also used as a performance-enhancing drug to promote muscle growth.

[0003] The inventors found in the process of implementing the present invention that: A Chinese patent with application number CN202310475067.X discloses a method for preparing dihydrotestosterone:

[0004] The method uses epiandrosterone as a raw material, obtains an intermediate through two steps of oxidation and selective protection, and then obtains dihydrotestosterone through two steps of reduction and deprotection from the intermediate.

[0005] However, this process has at least the following problems: expensive reagents and large amounts of reagents, heavy metal pollution, and harsh reaction temperature conditions. Summary of the invention

[0006] In order to solve the problems existing in the prior art, the present invention provides a method for preparing dihydrotestosterone and its oxidation intermediates.

[0007] Inventive concept: In view of the problems existing in the prior art, it is considered to provide a synthesis method of (5α)-androsten-3,17-dione (dihydrotestosterone oxide), using sodium hypochlorite solution as an oxidizing agent, which can avoid the use of expensive oxidizing agents such as PDC and IBX in the patent (CN202310475067.X); it also avoids the use of the currently widely used Jones reagent for oxidation, because of its complex operation, strong corrosiveness, and serious heavy metal pollution; at the same time, a synthesis method of dihydrotestosterone is provided, which is based on (5α)-androsten-3,17-dione (dihydrotestosterone oxide) using pyridine hydrochloride for selective etherification to obtain dihydrotestosterone etherate, and then reducing it with potassium borohydride or the like to obtain compound 5, and finally hydrolyzing it with hydrochloric acid to obtain dihydrotestosterone.

[0008] To this end, the technical solution of the present invention is: A method for preparing dihydrotestosterone and its intermediates, characterized in that: Using epiandrosterone as raw material, dihydrotestosterone (DHT) is obtained through oxidation, etherification, reduction hydrolysis and refining.

[0009] In the reaction route: compound 2 is epiandrosterone, compound 3 is dihydrotestosterone oxide, compound 3 is dihydrotestosterone oxide, compound 4 is dihydrotestosterone etherate, compound 5 is transition reaction liquid, and compound 1 is dihydrotestosterone crude product; The specific preparation method comprises the following steps: Step A: adding epiandrosterone to a reaction bottle, adding solvent 1, stirring and controlling the temperature, then adding an oxidant, controlling the temperature for reaction, monitoring the reaction by TLC, controlling the temperature, terminating the reaction, concentrating solvent 1, adding drinking water, stirring sufficiently, filtering, washing with water until neutral, discharging, and drying to obtain dihydrotestosterone oxide; Step B: adding the dihydrotestosterone oxide obtained in step A to a reaction bottle, adding solvent 2 and a dehydrating agent, stirring and controlling the temperature, then adding a catalyst, keeping the temperature for reaction, monitoring the reaction by TLC, terminating the reaction, cooling and crystallizing, filtering, and discharging to obtain dihydrotestosterone etherate; Step C: adding the dihydrotestosterone etherate obtained in step B to a reaction bottle, adding a solvent, stirring and controlling the temperature, then adding a reducing agent, controlling the temperature for reaction, after the reaction is completed by TLC monitoring, adding water to terminate the reaction, controlling the temperature, then dropping an acid, keeping the temperature for reaction, after the reaction is completed by TLC monitoring, adding a base to terminate the reaction, cooling and crystallizing, filtering, washing with water, and drying to obtain a crude dihydrotestosterone product; Step D: Add solvent 4 to the crude dihydrotestosterone obtained in step C, raise the temperature to reflux to dissolve, filter, raise the temperature of the filtrate to reflux, and then add a certain amount of water while maintaining reflux, after the addition is completed, keep the temperature at reflux, then cool down for crystallization, filter out the material, and dry to obtain a fine product of dihydrotestosterone.

[0010] Furthermore, the solvent added in step A is glacial acetic acid, or a mixed solvent of glacial acetic acid and dichloromethane, and the weight ratio of the solvent to the epiandrosterone is 3-4:1; wherein the weight ratio of glacial acetic acid to dichloromethane in the mixed solvent is between 1-1.5:2-5; the added oxidant is any one of sodium hypochlorite or hypochlorous acid reagent, the concentration of effective chlorine in hypochlorous acid and sodium hypochlorite is 9%-10%, preferably sodium hypochlorite, and the weight ratio of the added amount to the epiandrosterone is 3-4:1; the temperature of the oxidation reaction is controlled between 5-25°C, preferably 10-20°C; after the reaction is completed, the temperature is controlled at 5-15 ℃, terminate the reaction by adding one or more of sodium sulfite aqueous solution, sodium bisulfite aqueous solution, sodium thiosulfate aqueous solution, sodium pyrosulfite aqueous solution, etc., the solution concentration is between 5%-15%, and the weight ratio of the added amount to epiandrosterone is 0.5-3:1; stir at 20-30℃ for 30min; the amount of concentrated solvent one is 0.9-1.0 times the amount of added, and the concentration temperature is ±5℃ of the boiling point of the added solvent; the weight ratio of the added water to epiandrosterone is 6-8:1, filter, wash with water to neutral, discharge, dry at 70-90℃, and dry to obtain dihydrotestosterone oxide with a purity of ≥98%.

[0011] Furthermore, the solvent 2 in step B is anhydrous ethanol, and the weight ratio of the added amount to dihydrotestosterone oxide is 2-4:1; the dehydrating agent is triethyl orthoformate, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.6-1:1; the added catalyst is pyridine hydrochloride, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.1-1:1; the reaction temperature is 0-40°C, and the reaction time is between 1-24h; the crystallization temperature is 0-25°C, and the crystallization time is 0.5-3h; the material obtained after filtration and drying is dihydrotestosterone etherified, and the purity is ≥97%.

[0012] Further, the solvent three in step C is one of methanol, ethanol, tetrahydrofuran, etc., preferably methanol, and the weight ratio of the added amount to dihydrotestosterone oxide is 3-10:1; the reducing agent is one or more of potassium borohydride, sodium borohydride, sodium triacetoxyborohydride, etc., preferably potassium borohydride, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.1-0.4:1; the reaction temperature is between 0-40°C, and the reaction time is 1.0-5.0h; the weight ratio of the water used to terminate the reaction to dihydrotestosterone oxide is 0.5-1.5:1; after the water is added, the reaction is The liquid is cooled to between 0-15°C; an acid is added, which is one of hydrochloric acid and sulfuric acid, preferably hydrochloric acid, and the weight ratio of the added amount to the dihydrotestosterone oxide is 0.2-1.0:1; the reaction temperature is 0-40°C, and the reaction time is between 1-10h; after the reaction, an alkali is added, which is one or more of sodium hydroxide, sodium carbonate, and sodium bicarbonate, and the weight ratio of the added amount to the dihydrotestosterone oxide is 0.1-0.6:1; the temperature for cooling and crystallization is between 0-10°C, and the crystallization time is 0.5-2h; the baking temperature is 80-90°C, and after drying, a crude dihydrotestosterone product is obtained with a purity of ≥96%.

[0013] Furthermore, the solvent four in step D is one of methanol, ethanol, acetone, and isopropanol, preferably ethanol, and the weight ratio of the added amount to the crude dihydrotestosterone is 2-10:1; the amount of water added after reflux is 0.5-2.0 times the weight of the solvent four; the insulation reflux time is 1-3h, the cooling and crystallization temperature is 0-10°C, and the crystallization time is 0.5-3h; and the dihydrotestosterone is refined to obtain a purity ≥99%.

[0014] Beneficial effects: Compared with the prior art, the present invention provides a method for preparing dihydrotestosterone and its intermediates, which also uses epiandrosterone as a raw material to synthesize dihydrotestosterone through oxidation, etherification, reduction and hydrolysis. The method is simple and easy to operate, has the characteristics of high product purity, high material utilization, low production cost and good product quality, and can enhance the core competitiveness of the product; at the same time, it reduces the amount of process waste, reduces the cost of solid waste treatment and reduces environmental pollution. DETAILED DESCRIPTION

[0015] The technical solution of the present invention is clearly and completely described below through specific embodiments, but the embodiments should not be construed as limiting the present invention.

[0016] The present invention provides a method for preparing dihydrotestosterone oxide, and the reaction scheme is as follows:

[0017] In the reaction scheme: compound 2 is epiandrosterone, and compound 3 is dihydrotestosterone oxide; The method comprises the following steps: Step A: adding epiandrosterone to a reaction bottle, adding solvent 1, stirring and controlling the temperature, then adding an oxidant, controlling the temperature for reaction, monitoring the reaction by TLC, controlling the temperature, terminating the reaction, concentrating solvent 1, adding drinking water, stirring sufficiently, filtering, washing with water until neutral, discharging, and drying to obtain dihydrotestosterone oxide; In an embodiment of the present invention, the solvent added in step A is glacial acetic acid, or a mixed solvent of glacial acetic acid and dichloromethane, and the weight ratio of the solvent to epiandrosterone is 3-4:1; wherein the weight ratio of glacial acetic acid to dichloromethane in the mixed solvent is between 1-1.5:2-5; the added oxidant is any one of sodium hypochlorite or hypochlorous acid reagent, the concentration of effective chlorine in hypochlorous acid and sodium hypochlorite is 9%-10%, preferably sodium hypochlorite, and the weight ratio of the added amount to epiandrosterone is 3-4:1; the temperature of the oxidation reaction is controlled between 5-25°C, preferably 10-20°C; after the reaction is completed, the temperature is controlled at 5- 15°C, the reaction is terminated by adding one or more of sodium sulfite aqueous solution, sodium bisulfite aqueous solution, sodium thiosulfate aqueous solution, sodium pyrosulfite aqueous solution, etc., the solution concentration is between 5% and 15%, and the weight ratio of the added amount to epiandrosterone is 0.5-3:1; stirring at 20-30°C for 30 minutes; the amount of concentrated solvent one is 0.9-1.0 times the amount of added, and the concentration temperature is ±5°C of the boiling point of the added solvent; the weight ratio of the added water to epiandrosterone is 6-8:1, filtering, washing with water to neutrality, discharging, drying temperature: 70-90°C, drying to obtain dihydrotestosterone oxide, with a purity of ≥98%.

[0018] The present invention provides a method for preparing a dihydrotestosterone dihydrotestosterone etherate, and the reaction scheme is as follows:

[0019] In the reaction route: compound 3 is dihydrotestosterone oxide, and compound 4 is dihydrotestosterone etherate; The method comprises the following steps: Step B: adding the dihydrotestosterone oxide obtained in step A to a reaction bottle, adding solvent 2 and a dehydrating agent, stirring and controlling the temperature, then adding a catalyst, keeping the temperature for reaction, monitoring the reaction by TLC, terminating the reaction, cooling and crystallizing, filtering, and discharging to obtain dihydrotestosterone etherate; In an embodiment of the present invention, the second solvent in step B is anhydrous ethanol, and the weight ratio of the added amount to dihydrotestosterone oxide is 2-4:1; the dehydrating agent is triethyl orthoformate, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.6-1:1; the added catalyst is pyridine hydrochloride, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.1-1:1; the reaction temperature is 0-40°C, and the reaction time is between 1-24h; the crystallization temperature is 0-25°C, and the crystallization time is 0.5-3h; the material obtained after filtration and drying is dihydrotestosterone etherified, and the purity is ≥97%.

[0020] The present invention provides a method for preparing crude dihydrotestosterone and refined dihydrotestosterone, and the reaction scheme is as follows:

[0021]

[0022] In the reaction route: compound 4 is a dihydrotestosterone etherified product, compound 5 is a transition reaction liquid, and compound 1 is a dihydrotestosterone crude product; The method comprises the following steps: Step C: adding the dihydrotestosterone etherate in step B to a reaction bottle, adding a solvent, stirring and controlling the temperature, then adding a reducing agent, controlling the temperature for reaction, and obtaining a transition reaction solution of compound 5 after the reaction is completed by TLC monitoring; adding water to the transition reaction solution of compound 5 without post-treatment, controlling the temperature, and then dropping an acid, and reacting at the same temperature. After the reaction is completed by TLC monitoring, adding a base to terminate the reaction, cooling and crystallizing, filtering, washing with water, and drying to obtain a crude dihydrotestosterone product; In an embodiment of the present invention, the solvent three in step C is one of methanol, ethanol, tetrahydrofuran, etc., preferably methanol, and the weight ratio of the added amount to dihydrotestosterone oxide is 3-10:1; the reducing agent is one or more of potassium borohydride, sodium borohydride, sodium triacetoxyborohydride, etc., preferably potassium borohydride, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.1-0.4:1; the reaction temperature is between 0-40°C, and the reaction time is 1.0-5.0h; the weight ratio of the water used to terminate the reaction to dihydrotestosterone oxide is 0.5-1.5:1; the system obtained after the water addition is terminated is compound 5 reaction liquid; cooling the reaction liquid to between 0-15°C; adding an acid selected from hydrochloric acid and sulfuric acid, preferably hydrochloric acid, with the weight ratio of the added amount to dihydrotestosterone oxide being 0.2-1.0:1; the reaction temperature being 0-40°C, and the reaction time being between 1-10h; adding an alkali selected from one or more selected from sodium hydroxide, sodium carbonate, and sodium bicarbonate after the reaction, with the weight ratio of the added amount to dihydrotestosterone oxide being 0.1-0.6:1; the temperature for cooling and crystallization being between 0-10°C, and the crystallization time being 0.5-2h; the baking temperature being 80-90°C, and the material obtained after drying is compound 1: dihydrotestosterone crude product, with a purity of ≥96%.

[0023] The present invention provides a method for purifying dihydrotestosterone, and the refining method is as follows: Step D: Add solvent 4 to the crude dihydrotestosterone in step C, raise the temperature to reflux to dissolve, filter, raise the temperature of the filtrate to reflux, then add a certain amount of water while maintaining reflux, after the addition is completed, keep the temperature to reflux, then cool down for crystallization, filter out the material by suction, and dry to obtain the fine product of compound 1: fine product of dihydrotestosterone; In some embodiments of the present invention, the solvent four in step D is one of methanol, ethanol, acetone, and isopropanol, preferably ethanol, and the weight ratio of the added amount to the crude dihydrotestosterone is 2-10: 1; the amount of water added after reflux is 0.5-2.0 times the weight of the solvent; the insulation reflux time is 1-3h, the temperature of cooling and crystallization is 0-10°C, and the crystallization time is 0.5-3h; and dihydrotestosterone is refined to obtain a purity ≥99%.

[0024] Embodiment 1: (1) Add epiandrosterone (100 g, 344.3 mmol) and 300 g glacial acetic acid to a reaction flask to dissolve, control the temperature at 10°C and dropwise add 300 g of sodium hypochlorite solution, keep the temperature at 10°C and stir for 1-2 h, monitor the reaction until complete, control the temperature to 5°C, add 100 g of 10% sodium sulfite, continue to control the temperature to 20°C and stir for 30 min, then increase the temperature and concentrate to obtain 290 g of glacial acetic acid. After concentration, add 600 g of drinking water, stir sufficiently, filter at room temperature, wash with water until neutral, and dry at 80°C to obtain dihydrotestosterone oxide (93 g, purity 98.4%); (2) Add the dihydrotestosterone oxide obtained in (1) to the reaction flask, add anhydrous ethanol (186 g), stir, then add triethyl orthoformate (93 g), stir and control the temperature to 40°C, add pyridine hydrochloride (9.3 g), keep the temperature for 4 hours, after TLC confirms the completion of the reaction, cool to 0°C, crystallize for 1 hour, filter and dry to obtain dihydrotestosterone etherate (wet material 103.1 g, purity 97.8%); (3) Add dihydrotestosterone etherate obtained in (2) to the reaction flask, add methanol (279 g), stir and cool to 0°C, add potassium borohydride (18.6 g), keep warm for 5 hours, TLC, confirm the completion of the reaction, slowly add drinking water (139.5 g); after the addition, control the temperature to 0°C, drop hydrochloric acid (55.8 g), after the addition is complete, keep warm at 0°C for 10 hours; after TLC confirms the completion of the reaction, add sodium hydroxide (18.6 g), stir sufficiently, cool to 0°C, crystallize for 0.5 hours, filter, wash the filter cake with water until it is neutral, drain and dry, and dry at 90°C to obtain compound 1: dihydrotestosterone crude product (79.05 g, purity 98.2%); (4) Add compound 1 obtained in (3) to the reaction flask, add ethanol (158.1 g), stir and heat to reflux to dissolve, filter, keep the filtrate at reflux, drop purified water (79.05 g), keep the addition at reflux for 1 h, then cool to 0 ° C for crystallization for 3 h, filter, drain the material, and dry at 90 ° C to obtain the final dihydrotestosterone concentrate (72.5 g, purity 99.58%).

[0025] Embodiment 2: (1) Add epiandrosterone (100 g, 344.3 mmol), 100 g glacial acetic acid and 200 g dichloromethane to a reaction flask to dissolve, control the temperature at 10°C and dropwise add 300 g sodium hypochlorite solution, keep the temperature at 10°C and stir for 1-2 h, monitor the reaction to be complete, control the temperature to 10°C, add 75 g of 15% sodium bisulfite aqueous solution, continue to control the temperature to 25°C and stir for 30 min, then heat and concentrate to obtain 300 g of a mixed solvent of glacial acetic acid and dichloromethane, add 600 g of drinking water, stir sufficiently, heat and concentrate to obtain dichloromethane, cool to room temperature and filter, wash with water until neutral, and dry at 80°C to obtain dihydrotestosterone oxide (92.1 g, purity 98.1%); (2) Add the dihydrotestosterone oxide obtained in (1) to the reaction flask, add anhydrous ethanol (276.3 g), stir, then add triethyl orthoformate (55.3 g), stir and control the temperature to 20°C, add pyridine hydrochloride (46.05 g), keep the temperature for 2 hours, after TLC confirms the completion of the reaction, cool to 0°C, crystallize for 2 hours, filter and dry to obtain dihydrotestosterone etherate (wet material 102.8 g, purity 98.2%); (3) Add dihydrotestosterone etherate obtained in (2) to the reaction flask, add methanol (461 g), stir and cool to 5°C, add potassium borohydride (18.42 g), keep warm for 5 hours, TLC, confirm the completion of the reaction, slowly add drinking water (92.1 g); after the addition, control the temperature to 0°C, drop hydrochloric acid (55.2 g), after the addition is complete, keep warm at 10°C for 4 hours; after TLC confirms the completion of the reaction, add sodium carbonate (45.6 g), stir sufficiently, cool to 5°C, crystallize for 1.5 hours, filter, wash the filter cake with water until it is neutral, drain and dry, and dry at 90°C to obtain compound 1: dihydrotestosterone crude product (78.88 g, purity 98.33%); (4) Add compound 1 obtained in (3) to the reaction flask, add ethanol (394.4 g), stir and heat until reflux to dissolve, filter, keep the filtrate at reflux, drop purified water (394.4 g), after the addition is complete, keep the temperature at reflux for 1 hour, then cool to 0°C for crystallization for 2 hours, filter, drain the material, dry at 90°C, and finally obtain the final dihydrotestosterone fine product (72.0 g, purity 99.63%). The parts not described in detail in this specification are well known in the art.

[0026] It should be understood that those skilled in the art can make improvements or changes based on the above description, and all these improvements and changes should fall within the scope of protection of the appended claims of the present invention.

Claims

1. A method for preparing dihydrotestosterone and its intermediates, characterized in that: Using epiandrosterone as raw material, dihydrotestosterone (DHT) is obtained through oxidation, etherification, reduction hydrolysis and refining. The specific preparation method comprises the following steps: Step A: adding epiandrosterone to a reaction bottle, adding solvent 1, stirring and controlling the temperature, then adding an oxidant, controlling the temperature for reaction, monitoring the reaction by TLC, controlling the temperature, terminating the reaction, concentrating solvent 1, adding drinking water, stirring sufficiently, filtering, washing with water until neutral, discharging, and drying to obtain dihydrotestosterone oxide; Step B: adding the dihydrotestosterone oxide obtained in step A to a reaction bottle, adding solvent 2 and a dehydrating agent, stirring and controlling the temperature, then adding a catalyst, keeping the temperature for reaction, monitoring the reaction by TLC, terminating the reaction, cooling and crystallizing, filtering, and discharging to obtain dihydrotestosterone etherate; Step C: adding the dihydrotestosterone etherate obtained in step B to a reaction bottle, adding a solvent, stirring and controlling the temperature, then adding a reducing agent, controlling the temperature for reaction, after the reaction is completed by TLC monitoring, adding water to terminate the reaction, controlling the temperature, then dropping an acid, keeping the temperature for reaction, after the reaction is completed by TLC monitoring, adding a base to terminate the reaction, cooling and crystallizing, filtering, washing with water, and drying to obtain a crude dihydrotestosterone product; Step D: Add solvent 4 to the crude dihydrotestosterone obtained in step C, raise the temperature to reflux to dissolve, filter, raise the temperature of the filtrate to reflux, and then add a certain amount of water while maintaining reflux, after the addition is completed, keep the temperature at reflux, then cool down for crystallization, filter out the material, and dry to obtain a fine product of dihydrotestosterone.

2. A method for preparing dihydrotestosterone and an intermediate thereof according to claim 1, characterized in that: The solvent added in step A is glacial acetic acid, or a mixed solvent of glacial acetic acid and dichloromethane, and the weight ratio of the solvent to epiandrosterone is 3-4:1, wherein the weight ratio of glacial acetic acid to dichloromethane in the mixed solvent is between 1-1.5:2-5; the added oxidant is any one of sodium hypochlorite or hypochlorous acid reagent, the concentration of effective chlorine in hypochlorous acid or sodium hypochlorite is 9%-10%, preferably sodium hypochlorite, and the weight ratio of the added amount to epiandrosterone is 3-4:1; the temperature of the oxidation reaction is controlled between 5-25°C, preferably 10-20°C; after the reaction is completed, the temperature is controlled at 5-15°C, and the oxidant is passed through The reaction is terminated by adding one or more of sodium sulfite aqueous solution, sodium bisulfite aqueous solution, sodium thiosulfate aqueous solution, sodium pyrosulfite aqueous solution, etc., the solution concentration is between 5% and 15%, and the weight ratio of the added amount to epiandrosterone is 0.5-3:1; stirring at 20-30°C for 30 minutes; the amount of concentrated solvent one is 0.9-1.0 times the amount of added, and the concentration temperature is ±5°C of the boiling point of the added solvent; the weight ratio of the added water to epiandrosterone is 6-8:1, filtering, washing with water to neutrality, discharging, drying temperature: 70-90°C, and drying to obtain dihydrotestosterone oxide with a purity of ≥98%.

3. A method for preparing dihydrotestosterone and an intermediate thereof according to claim 1 or 2, characterized in that: The solvent 2 in step B is anhydrous ethanol, and the weight ratio of the added amount to dihydrotestosterone oxide is 2-4:1; the dehydrating agent is triethyl orthoformate, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.6-1:1; the added catalyst is pyridine hydrochloride, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.1-1:1; the reaction temperature is 0-40°C, and the reaction time is between 1-24h; the crystallization temperature is 0-25°C, and the crystallization time is 0.5-3h; the material obtained after suction filtration and drying is dihydrotestosterone etherified product with a purity of ≥97%.

4. A method for preparing dihydrotestosterone and an intermediate thereof according to claim 3, characterized in that: The solvent three in step C is one of methanol, ethanol, tetrahydrofuran, etc., preferably methanol, and the weight ratio of the added amount to dihydrotestosterone oxide is 3-10:1; the reducing agent is one or more of potassium borohydride, sodium borohydride, sodium triacetoxyborohydride, etc., preferably potassium borohydride, and the weight ratio of the added amount to dihydrotestosterone oxide is 0.1-0.4:1; the reaction temperature is between 0-40°C, and the reaction time is 1.0-5.0h; the weight ratio of the water used to terminate the reaction to dihydrotestosterone oxide is 0.5-1.5:1; after the water addition is terminated, the reaction solution is cooled The temperature of the reaction mixture is 0-15°C; the acid added is one of hydrochloric acid and sulfuric acid, preferably hydrochloric acid, and the weight ratio of the added amount to the dihydrotestosterone oxide is 0.2-1.0:1; the reaction temperature is 0-40°C, and the reaction time is between 1-10h; after the reaction, the base added is one or more of sodium hydroxide, sodium carbonate, and sodium bicarbonate, and the weight ratio of the added amount to the dihydrotestosterone oxide is 0.1-0.6:1; the temperature of cooling and crystallization is between 0-10°C, and the crystallization time is 0.5-2h; the baking temperature is 80-90°C, and after drying, a crude dihydrotestosterone product is obtained with a purity of ≥96%.

5. A method for preparing dihydrotestosterone and an intermediate thereof according to claim 1, 2 or 4, characterized in that: The solvent four in step D is one of methanol, ethanol, acetone, and isopropanol, preferably ethanol, and the weight ratio of the added amount to the crude dihydrotestosterone is 2-10:1; the amount of water added after reflux is 0.5-2.0 times the weight of the solvent four; the insulation reflux time is 1-3h, the temperature of cooling and crystallization is 0-10°C, and the crystallization time is 0.5-3h; and the dihydrotestosterone fine product is refined to obtain a purity of ≥99%.

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