Method for recycling dihydrotestosterone mother liquor and intermediate mother liquor thereof

Abstract

The invention discloses a method for recycling dihydrotestosterone mother liquor and intermediate mother liquor thereof, the dihydrotestosterone mother liquor and the intermediate mother liquor thereof are used as raw materials, the dihydrotestosterone (DHT) is obtained through hydrolysis or primary purification, oxidation, purification, etherification, reduction hydrolysis and refining, the purity of the obtained dihydrotestosterone is greater than or equal to 99%, and the effect of effective recycling is achieved. The method is simple and convenient to operate, easy to implement and high in recycling rate and efficiency.

Description

Technical Field

[0001] The invention relates to the technical field of steroid drug preparation, and in particular to a method for recycling dihydrotestosterone and its intermediate mother liquor. Background Art

[0002] Dihydrotestosterone, English name: Dihydrotestosterone, chemical name: 17β-hydroxy-5α-androstane-3-one, molecular formula: C 19 H 30 O2. Dihydrotestosterone can be produced directly by the testicles, or it can be converted from androgens and estrogens as precursors by surrounding tissues. It can promote the normal development of the external genitalia and prostate, play a positive role in the appearance and maintenance of secondary sexual characteristics, and promote the maturation of sperm in the epididymis. It is mainly used clinically for abnormal sexual differentiation caused by 5α-reductase deficiency and for differential diagnosis of benign prostate diseases. It is also of great significance to observe the efficacy of prostate tumors, explore the causes of sexual dysfunction, infertility, female hirsutism, etc.

[0003] The current method for producing dihydrotestosterone (DHT) is to use epiandrosterone as the raw material through oxidation, etherification, reduction, and hydrolysis. The synthesis route is as follows:

[0004] The inventors took the mother liquor of dihydrotestosterone synthesized by the above process and its intermediate mother liquor as the research objects. In the process of realizing the present invention, the inventors found that there are at least the following problems in the prior art: in the process of synthesizing dihydrotestosterone, about 0.5-3% of DHT-01 in the etherification step is not reacted thoroughly or degraded back, and after the reduction reaction, androstradiol and its isomers are generated; the reduction step also produces 17-hydroxy alcohol isomer impurities; these impurities will be enriched in the mother liquor after refining, and the refined DHT mother liquor contains DHT (50-70%), DHT-01 (5%-10%), DHT isomers In addition, the intermediate DHT-01 mother liquor contains DHT-01 (80-90%), DHT-00 (1-5%) and other impurities; the DHT-02 mother liquor contains DHT-02 (80-90%), DHT-01 (5-10%) and other impurities. The above mother liquors are enriched after multiple refinings and it is difficult to purify them again. Long-term production will accumulate more mother liquor solid waste and waste liquid. Therefore, the recycling of dihydrotestosterone mother liquor is very important. Summary of the invention

[0005] In order to solve the problems existing in the prior art, the present invention proposes a method for recycling dihydrotestosterone mother liquor and its intermediate mother liquor. The method has simple process and high product purity, which is beneficial to reducing the production cost of dihydrotestosterone, reducing the cost of treating solid waste and reducing environmental pollution.

[0006] To this end, the technical solution adopted by the present invention is: a method for recycling dihydrotestosterone mother liquor and its intermediate mother liquor, characterized in that: Using dihydrotestosterone and its intermediate mother liquor as raw materials, dihydrotestosterone (DHT) is obtained through hydrolysis or primary purification, oxidation, secondary purification, etherification, reduction hydrolysis and refining;

[0007] The specific processing method includes the following steps: Step A: adding dihydrotestosterone mother liquor and its intermediate mother liquor into a reaction bottle, adding solvent 1, stirring and heating, then adding an acid solution for hydrolysis, keeping the temperature for reaction for a period of time, adding an appropriate amount of dilute alkali to adjust the pH of the system, heating and concentrating part of the solvent, then cooling and stirring for crystallization, filtering out the material by suction, beating and washing with water, and then draining the material to obtain a crude dihydrotestosterone mixture; adding solvent 2 to the crude dihydrotestosterone mixture, heating to reflux to dissolve, then adding a certain amount of water while maintaining reflux, after the addition is completed, keeping the temperature and reflux, then cooling and crystallizing, filtering out the material by suction, and drying to obtain a fine dihydrotestosterone mixture; Step B: adding solvent three to the fine product of dihydrotestosterone mixture in step A, controlling the temperature, adding an oxidant and a catalyst, and reacting under controlled temperature; after the reaction is completed, terminating the reaction, concentrating solvent three, filtering, washing with water to neutralize, and discharging to obtain a crude product of dihydrotestosterone oxide; taking the crude product of dihydrotestosterone oxide, adding solvent four, heating to reflux to dissolve, and then adding a certain amount of water while maintaining reflux, after the addition is completed, keeping the temperature to reflux, then cooling for crystallization, filtering and discharging, and drying to obtain a fine product of dihydrotestosterone oxide; Step C: adding solvent 5, a catalyst and a dehydrating agent to the fine dihydrotestosterone oxide prepared in step B, carrying out a reaction at a temperature-keeping temperature, cooling the temperature for crystallization, and filtering by suction to obtain a dihydrotestosterone etherate; Step D: adding solvent VI and a reducing agent to the dihydrotestosterone etherate in step C, and reacting at a controlled temperature. After the reaction is completed, terminating the reaction; controlling the temperature, adding an acid, and continuing the controlled temperature reaction. After the reaction is completed, adding a base to terminate the reaction, cooling and crystallizing, filtering, and washing with water to obtain a crude dihydrotestosterone product; Step E: Add solvent seven to the crude dihydrotestosterone in step D, raise the temperature to reflux and 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 at reflux, then cool down for crystallization, filter out the material, and dry to obtain a fine product of dihydrotestosterone.

[0008] Preferably, the solvent 1 in step A is one of water-soluble solvents such as methanol, ethanol, acetone, etc., and the weight ratio of the solvent to the mother liquor of dihydrotestosterone and its intermediate is 2-15:1; the acid added for hydrolysis is one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, etc., with a concentration of 5%-50%, and the weight ratio of the amount used to the material is 0.5-5:1; the insulation reaction time is 0.5-5h, and the reaction temperature is between 10-80°C; the base used to adjust the pH is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc., with a concentration of 5%-40%, and the pH is required to be adjusted to pH = 6-7; the concentrated solvent concentration is 0.5-1.0W of the added amount, and the concentration temperature is 10-80°C. The temperature of the boiling point of the added solvent is ±5°C; the cooling and crystallization temperature is controlled at 0-30°C, the crystallization time is 1-5h, suction filtering, and drying to obtain a crude dihydrotestosterone mixture (wet product); the solvent II added to the crude dihydrotestosterone mixture is one or more water-soluble solvents such as methanol, ethanol, acetone, isopropanol, etc., and the weight ratio to the dihydrotestosterone mother liquor and its intermediate mother liquor is 2-10:1; the reflux time is 0.5-1h; while maintaining the reflux, 0.5-1.0 times the weight of drinking water of the solvent II is added dropwise, and after the addition is completed, the reflux is maintained for 0.5-1h, and then the crystallization temperature is 0-25°C, and the crystallization time is 0.5-3h; the drying temperature is: 60-90°C, and after drying, a fine dihydrotestosterone mixture is obtained.

[0009] Preferably, the solvent three in step B is one or more of toluene, dichloromethane, chloroform, acetone and other solvents, and the weight ratio of the solvent to the weight of the dihydrotestosterone mixture is 1-20:1; the added catalyst is one or more of glacial acetic acid, propionic acid, carbonic acid, sulfuric acid, etc., and the added amount is 0.1-5:1 to the weight ratio of the dihydrotestosterone mixture; the added oxidant is one or more of Jones reagent, hypochlorous acid, sodium hypochlorite, etc., wherein the concentration of effective chlorine in hypochlorous acid and sodium hypochlorite is 9%-10%, and the added amount is 1-2:1 to the weight ratio of the dihydrotestosterone mixture; the temperature range of the temperature control reaction is 0-45°C, and the reaction time is 1-10h; after the reaction is completed, the reaction is terminated, and one or more of sodium sulfite aqueous solution, sodium bisulfite aqueous solution, sodium thiosulfate aqueous solution, sodium pyrosulfite aqueous solution, etc. are added, and the solution concentration is 5%-15%. The weight ratio of the added amount to the fine dihydrotestosterone mixture is 0.5-3:1; stirring at 20-30℃ for 30min, then adding drinking water in a ratio of 1.0-3.0:1, heating and concentrating; the concentration temperature is ±5℃ of the boiling point of the added solvent; after concentration, suction filtration, the filter cake is washed with water until neutral, and the crude dihydrotestosterone oxide (wet product) is obtained; taking the crude dihydrotestosterone oxide, adding solvent four, which is one or more of methanol, ethanol, acetone, isopropanol and other water-soluble solvents, and the weight ratio to the fine dihydrotestosterone mixture is 2-10:1; reflux time is 0.5-1h; then dripping 0.5-1.0 times the weight of drinking water in the solvent four under reflux state, keeping reflux for 0.5-1h after dripping, and then cooling and crystallizing, the crystallization temperature is 0-25℃, and the crystallization time is 0.5-3h; the drying temperature is: 60-90℃; after drying, the fine dihydrotestosterone oxide is obtained, and the purity is ≥98%.

[0010] Preferably, the solvent five in step C is one of methanol and ethanol, preferably ethanol; the weight ratio of the added amount to the dihydrotestosterone oxide product is 1-5:1; the catalyst is one or more of pyridine hydrochloride, p-toluenesulfonate, pyridine p-toluenesulfonate, etc., and the weight ratio of the added amount to the dihydrotestosterone oxide product is 0.1-1.0:1; the dehydrating agent is one of triethyl orthoformate and trimethyl orthoformate, and the weight ratio of the added amount to the dihydrotestosterone oxide product is 0.5-2.0:1; 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 obtained material is dihydrotestosterone etherified product with a purity of ≥98%.

[0011] Preferably, the solvent six in step D is one of methanol, ethanol, tetrahydrofuran, etc., and the weight ratio of the added amount to the dihydrotestosterone oxide product is 3-10:1; the reducing agent is one or more of potassium borohydride, sodium borohydride, sodium triacetoxyborohydride, etc., and the weight ratio of the added amount to the dihydrotestosterone oxide product is 0.1-0.5:1; the reaction temperature is between 0-40°C, and the reaction time is 1.0-5.0h; the method for terminating the reaction after the reaction is completed is to add drinking water, and the weight ratio of the water to the dihydrotestosterone oxide product is 0.5-1 .5:1; control the temperature to be 0-15℃; add one of hydrochloric acid and sulfuric acid as the acid, and the weight ratio of the added amount to the fine dihydrotestosterone oxide is 0.2-1.0:1; the reaction temperature is 0-40℃, and the reaction time is between 1-10h; after the reaction, add one or more of sodium hydroxide, sodium carbonate, and sodium bicarbonate as the alkali, and the weight ratio of the added amount to the fine dihydrotestosterone oxide is 0.1-0.6:1; the temperature for cooling and crystallization is between 0-10℃, and the crystallization time is 0.5-2h; the obtained material is a crude dihydrotestosterone product with a purity ≥96%.

[0012] Preferably, the solvent seven in step E is one of methanol, ethanol, acetone and isopropanol, 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 seven; the temperature for cooling and crystallization is 0-10°C, and the crystallization time is 0.5-3h; and dihydrotestosterone is refined to obtain a purity of ≥99%.

[0013] Beneficial effects: The present invention provides a method for recycling a dihydrotestosterone mother liquor and an intermediate mother liquor thereof. In step A, the intermediate DHT-02 in the mother liquor is hydrolyzed into DHT-01 by hydrolysis and refining, and the oily impurities, water-soluble impurities and salts in the mother liquor are removed; in step B, the dihydrotestosterone isomers, androstenol and its isomers in the mother liquor are mainly oxidized into DHT-01 by oxidation, and the intermediate is further purified by purification; in steps C, D and E, the synthesis and purity improvement of dihydrotestosterone are achieved by synthesis and refining; This method is easy to operate, environmentally friendly, and efficient, and has the following advantages: (1) high recycling rate, qualified products, and DHT purity ≥ 99%; (2) the treatment method is simple and easy to operate, with a large processing volume; (3) cost savings and reduced environmental pollution. DETAILED DESCRIPTION

[0014] 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.

[0015] Embodiment 1: (1) Add 100 g of a mixture of a dihydrotestosterone mother liquor and an intermediate mother liquor to a reaction flask, add 200 g of methanol and stir evenly, then add 50 g of a 25% aqueous sulfuric acid solution, stir and heat to 40°C, and maintain for 1 hour; then add 75 g of a 25% sodium hydroxide solution, adjust to pH = 6, control the temperature to concentrate 100 g of methanol, cool to 10°C, crystallize for 2 hours, and filter to obtain a crude dihydrotestosterone mixture (wet product); add the crude dihydrotestosterone mixture wet material to a reaction flask, add 200 g of methanol, stir and heat to reflux for 1 hour, maintain reflux, drop 100 g of drinking water, continue to reflux for 1 hour after the dripping is complete, cool to 20°C to crystallize for 1 hour, filter, put into an oven at 60°C to dry to constant weight, collect 91 g of the material, and obtain a fine dihydrotestosterone mixture; (2) Add 91 g of the dihydrotestosterone mixture obtained in (1) to the reaction flask, add 455 g of dichloromethane, stir to dissolve, then add 91 g of glacial acetic acid to the reaction flask, stir evenly, control the temperature at 10°C, and slowly add 182 g of sodium hypochlorite; control the temperature at 10°C for 2 hours, take a TLC sample, and after confirming that the reaction is complete, control the temperature to 30°C , add 91g of 5% sodium bisulfite and stir for 30min, then add 91g of drinking water, heat to 40℃ and concentrate dichloromethane; filter by suction, wash with water to obtain crude dihydrotestosterone oxide; add crude dihydrotestosterone oxide to the reaction bottle, add 182g of methanol, stir and heat to reflux for 0.5h, keep reflux, add 91g of drinking water dropwise, continue to reflux for 30min, then cool to 20℃ and crystallize for 1h, filter by suction, and discharge; put into the oven at 60-70℃ and dry to constant weight, collect 86.5g of dihydrotestosterone oxide, and obtain fine product with a purity of 98.3%; (3) Add 86.5 g of the refined dihydrotestosterone oxide obtained in (2), 173 g of ethanol, 8.65 g of pyridine hydrochloride and 86.5 g of triethyl orthoformate into the reaction flask, stir and control the temperature to 20° C. to react for 8 h. After the reaction is completed and terminated, cool to 0° C. to crystallize for 0.5 h, filter with suction, and obtain 94.5 g of dihydrotestosterone etherate wet material with a purity of 98.55%; (4) Add 94.5 g of the wet material of dihydrotestosterone etherate obtained in (3) to the reaction flask, add 433 g of ethanol, control the temperature at 5°C and stir, slowly add 8.65 g of sodium borohydride, after the addition is completed, keep the temperature to react for 1 hour, and confirm the completion of the reaction by TLC; slowly add 86.5 g of water to terminate the reaction; after the addition of water is completed, control the temperature to 5°C, dropwise add 25.95 g of hydrochloric acid, control the temperature to 30°C and react for 2 hours, after TLC confirms the completion of the reaction, add 17.3 g of sodium carbonate to terminate the reaction, after the addition is completed, cool to 10°C and crystallize for 2 hours, filter, and wash thoroughly to obtain 78.1 g of crude dihydrotestosterone with a purity of 96.85%; (5) Add 78.1 g of the crude dihydrotestosterone wet material in (4) to the reaction flask, add 157 g of ethanol, stir and heat to reflux to dissolve, filter, and add 78.1 g of purified water dropwise to the filtrate while maintaining reflux. After the addition is complete, slowly cool to 5°C to crystallize for 3 hours, filter, drench the cake with a small amount of ethanol, drain the material, and dry it at 80-90°C. The material is 72.2 g, a fine product of dihydrotestosterone, with a purity of 99.2%. Embodiment 2: (1) Add 100 g of a mixture of a dihydrotestosterone mother liquor and an intermediate mother liquor to a reaction flask, add 800 g of ethanol and stir evenly, then add 200 g of a 9% hydrochloric acid aqueous solution, stir and heat to 80°C, and maintain for 0.5 h; then add 100 g of a 10% potassium hydroxide solution, adjust to pH = 7, control the temperature to concentrate 500 g of ethanol, cool to 20°C, crystallize for 1 h, and filter to obtain a crude dihydrotestosterone mixture (wet product); add the crude dihydrotestosterone mixture wet material to a reaction flask, add 300 g of ethanol, stir and heat to reflux for 1 h, maintain reflux, drop 150 g of drinking water, continue to reflux for 0.5 h after the dripping is complete, then cool to 0°C and crystallize for 2 h, filter, and dry in an oven at 80°C to constant weight, collect 90.2 g of the material, and obtain a fine dihydrotestosterone mixture; (2) Add 90.2 g of the dihydrotestosterone mixture obtained in (1) to the reaction flask, add 360 g of chloroform, stir to dissolve, then add 9.1 g of glacial acetic acid to the reaction flask, stir evenly, control the temperature at 0°C, and slowly add 180 g of hypochlorous acid; control the temperature at 0-10°C to react for 6 hours, take a TLC sample, and after confirming that the reaction is complete, control the temperature to 20°C , add 46g of 10% sodium sulfite, stir for 30min, then add 270g of drinking water, heat to 60℃ and concentrate dichloromethane; filter with suction, wash with water to obtain crude dihydrotestosterone oxide; add the crude dihydrotestosterone oxide to the reaction bottle, add 181g of ethanol, stir and heat to reflux for 1.0h, keep reflux, add 91g of drinking water dropwise, continue to reflux for 30min, then cool to 10℃ and crystallize for 2.0h, filter with suction, and discharge; put into the oven to dry at 80-90℃ to constant weight, collect 87.0g of material, and obtain fine dihydrotestosterone oxide with a purity of ≥98.4%; (3) Add 87.0 g of the refined dihydrotestosterone oxide obtained in (2), 261 g of ethanol, 17.4 g of p-toluenesulfonic acid and 86.5 g of triethyl orthoformate into the reaction flask, stir and control the temperature to 20° C. to react for 12 h. After the reaction is completed and terminated, cool to 5° C. to crystallize for 1.0 h, filter and obtain 95.5 g of dihydrotestosterone etherate wet material with a purity of 98.68%; (4) Add 95.5 g of the wet material of dihydrotestosterone etherate obtained in (3) to the reaction flask, add 261 g of methanol, control the temperature at 30°C and stir, slowly add 17.4 g of potassium borohydride, after the addition is completed, keep the temperature to react for 2.0 h, and confirm the completion of the reaction by TLC; slowly add 131 g of water to terminate the reaction; control the temperature to 0°C, add 60.9 g of hydrochloric acid, control the temperature at 10°C and react for 5 h, after TLC confirms the completion of the reaction, add 34.8 g of sodium hydroxide to terminate the reaction, after the addition is completed, cool to 10°C and crystallize for 2 h, filter with suction, and wash thoroughly to obtain 78.5 g of crude dihydrotestosterone with a purity of 97%; (5) Add 78.5 g of the crude dihydrotestosterone wet material in (4) to the reaction flask, add 393 g of methanol, stir and heat to reflux to dissolve, filter, and add 786 g of purified water dropwise to the filtrate while maintaining reflux. After the addition is complete, slowly cool to 0°C to crystallize for 1 hour, filter, add a small amount of methanol to the cake, drain the material, and dry it at 80-90°C. The material is 73.5 g, a fine product of dihydrotestosterone, with a purity of 99.35%; Embodiment three: (1) Add 100g of a mixture of a dihydrotestosterone mother liquor and an intermediate mother liquor to a reaction flask, add 800g of acetone and stir evenly, then add 500g of a 50% acetic acid aqueous solution, stir and heat to 70°C, and maintain for 5h; then add 100g of a 30% sodium carbonate solution, adjust to pH=6.5, control the temperature to concentrate 300g of acetone, cool to 30°C, crystallize for 1.0h, and filter to obtain a crude dihydrotestosterone mixture (wet product); add the crude dihydrotestosterone mixture wet material to a reaction flask, add 500g of acetone, stir and heat to reflux for 1h, maintain reflux, drop 250g of drinking water, continue to reflux for 1h after the dripping is complete, then cool to 0°C and crystallize for 3h, filter, and dry in an oven at 60°C to constant weight, collect 93.1g of the material, and obtain a fine dihydrotestosterone mixture; (2) Add 93.1 g of the dihydrotestosterone mixture obtained in (1) to a reaction flask, add 1397 g of acetone, stir to dissolve, then add 9.31 g of sulfuric acid to the reaction flask, stir evenly, control the temperature at 0°C, and slowly add 93.1 g of Jones reagent; control the temperature at 30°C to react for 6 h, take a TLC sample, and after confirming that the reaction is complete, control the temperature to 25°C, filter, add 46.5 g of 15% sodium thiosulfate to the filtrate, stir for 30 min, then add 279 g of drinking water, Raise the temperature to 60°C to concentrate acetone; filter with suction, wash with water to obtain crude dihydrotestosterone oxide (wet product); add the crude dihydrotestosterone oxide to a reaction bottle, add 931g isopropanol, stir and heat to reflux for 1.0h, keep reflux, add 466g drinking water dropwise, continue reflux for 30min, then cool to 0°C for crystallization for 2.0h, filter with suction, and discharge; put into an oven to dry at 80-90°C to constant weight, collect 83.5g of material, and obtain fine dihydrotestosterone oxide with a purity of 98.15%; (3) Add 83.5 g of the refined dihydrotestosterone oxide obtained in (2), 334 g of methanol, 41.75 g of pyridine p-toluenesulfonate and 167 g of trimethyl orthoformate into a reaction flask, stir and control the temperature to 40°C for 24 h. After the reaction is completed and terminated, cool to 0°C for crystallization for 3.0 h, filter and obtain 86.5 g of dihydrotestosterone etherate wet material with a purity of 99.05%; (4) Add 86.5 g of the wet material of dihydrotestosterone etherate obtained in (3) to the reaction flask, add 501 g of tetrahydrofuran, control the temperature at 40°C and stir, slowly add 16.7 g of sodium triacetoxyborohydride, after the addition is completed, keep the temperature to react for 5 h, and confirm the completion of the reaction by TLC; slowly add 83.5 g of water to terminate the reaction; control the temperature to 0°C, add 25.1 g of sulfuric acid, control the temperature at 40°C to react for 10 h, after TLC confirms the completion of the reaction, add 16.7 g of sodium hydroxide to terminate the reaction, after the addition is completed, cool to 0°C to crystallize for 1.0 h, filter with suction, and wash thoroughly with water to obtain 73.4 g of crude dihydrotestosterone with a purity of 97.15%; (5) Add 73.4 g of the crude dihydrotestosterone wet material in (4) to the reaction flask, add 294 g of acetone, stir and heat to reflux to dissolve, filter, and add 147 g of purified water dropwise to the filtrate while maintaining reflux. After the addition is complete, slowly cool to 10°C to crystallize for 3 hours, filter, drench the cake with a small amount of acetone, drain the material, and dry it at 80-90°C. The material is 69.8 g, which is a fine product of dihydrotestosterone with a purity of 99.42%. Parts not described in detail in this specification are well-known technologies in the art.

[0016] 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 recycling a dihydrotestosterone mother liquor and an intermediate mother liquor thereof, characterized in that: Using dihydrotestosterone and its intermediate mother liquor as raw materials, dihydrotestosterone (DHT) is obtained through hydrolysis or primary purification, oxidation, secondary purification, etherification, reduction hydrolysis and refining; The specific processing method includes the following steps: Step A: adding dihydrotestosterone mother liquor and its intermediate mother liquor into a reaction bottle, adding solvent 1, stirring and heating, then adding an acid solution for hydrolysis, keeping the temperature for reaction for a period of time, adding an appropriate amount of dilute alkali to adjust the pH of the system, heating and concentrating part of the solvent, then cooling and stirring for crystallization, filtering out the material by suction, beating and washing with water, and then draining the material to obtain a crude dihydrotestosterone mixture; adding solvent 2 to the crude dihydrotestosterone mixture, heating to reflux to dissolve, then adding a certain amount of water while maintaining reflux, after the addition is completed, keeping the temperature and reflux, then cooling and crystallizing, filtering out the material by suction, and drying to obtain a fine dihydrotestosterone mixture; Step B: adding solvent three to the fine product of dihydrotestosterone mixture in step A, controlling the temperature, adding an oxidant and a catalyst, and reacting under controlled temperature; after the reaction is completed, terminating the reaction, concentrating solvent three, filtering, washing with water to neutralize, and discharging to obtain a crude product of dihydrotestosterone oxide; taking the crude product of dihydrotestosterone oxide, adding solvent four, heating to reflux to dissolve, and then adding a certain amount of water while maintaining reflux, after the addition is completed, keeping the temperature to reflux, then cooling for crystallization, filtering and discharging, and drying to obtain a fine product of dihydrotestosterone oxide; Step C: adding solvent 5, a catalyst and a dehydrating agent to the fine dihydrotestosterone oxide prepared in step B, carrying out a reaction at a temperature-keeping temperature, cooling the temperature for crystallization, and filtering by suction to obtain a dihydrotestosterone etherate; Step D: adding solvent VI and a reducing agent to the dihydrotestosterone etherate in step C, and reacting at a controlled temperature. After the reaction is completed, terminating the reaction; controlling the temperature, adding an acid, and continuing the controlled temperature reaction. After the reaction is completed, adding a base to terminate the reaction, cooling and crystallizing, filtering, and washing with water to obtain a crude dihydrotestosterone product; Step E: Add solvent seven to the crude dihydrotestosterone in step D, raise the temperature to reflux and 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 at reflux, then cool down for crystallization, filter out the material, and dry to obtain a fine product of dihydrotestosterone.

2. A method for recycling a dihydrotestosterone mother liquor and an intermediate mother liquor thereof according to claim 1, characterized in that: The solvent 1 in step A is one of water-soluble solvents such as methanol, ethanol, acetone, etc., and the weight ratio of the solvent to the mother liquor of dihydrotestosterone and its intermediate is 2-15:1; the acid added for hydrolysis is one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, etc., the concentration is between 5%-50%, and the weight ratio of the amount used to the material is 0.5-5:1; the heat preservation reaction time is 0.5-5h, and the reaction temperature is between 10-80°C; the alkali used for adjusting the pH is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc., the concentration is between 5%-40%, and the pH is required to be adjusted to between pH=6-7; the concentrated solvent concentration is 0.5-1.0W of the added amount, and the concentration temperature is 10-80°C. The temperature of the boiling point of the added solvent is ±5°C; the cooling and crystallization temperature is controlled at 0-30°C, the crystallization time is 1-5h, suction filtering, and drying to obtain a crude dihydrotestosterone mixture; the solvent II added to the crude dihydrotestosterone mixture is one or more water-soluble solvents such as methanol, ethanol, acetone, isopropanol, etc., and the weight ratio of the solvent II to the dihydrotestosterone mother liquor and its intermediate mother liquor is 2-10:1; the reflux time is 0.5-1h; while maintaining the reflux, 0.5-1.0 times of drinking water is added dropwise, and after the addition is completed, the reflux is maintained for 0.5-1h, and then the crystallization temperature is 0-25°C, and the crystallization time is 0.5-3h; the drying temperature is: 60-90°C, and after drying, a fine dihydrotestosterone mixture is obtained.

3. A method for recycling a dihydrotestosterone mother liquor and an intermediate mother liquor thereof according to claim 1 or 2, characterized in that: The solvent three in step B is one or more of toluene, dichloromethane, chloroform, acetone and other solvents, and the weight ratio of the solvent to the weight of the dihydrotestosterone mixture is 1-20:1; the added catalyst is one or more of glacial acetic acid, propionic acid, carbonic acid, sulfuric acid and the like, and the added amount is 0.1-5:1 to the weight ratio of the dihydrotestosterone mixture; the added oxidant is one or more of Jones reagent, hypochlorous acid, sodium hypochlorite and the like, wherein the concentration of effective chlorine in hypochlorous acid and sodium hypochlorite is 9%-10%, and the added amount is 1-2:1 to the weight ratio of the dihydrotestosterone mixture; the temperature range of the temperature control reaction is 0-45°C, and the reaction time is 1-10h; after the reaction is completed, 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 and the like, and the solution concentration is between 5% and 15%. The weight ratio of the added amount to the fine dihydrotestosterone mixture is 0.5-3:1; stirring at 20-30℃ for 30min, then adding drinking water in a ratio of 1.0-3.0:1, heating and concentrating; the concentration temperature is ±5℃ of the boiling point of the added solvent; after concentration, suction filtration, the filter cake is washed with water until neutral, and the crude dihydrotestosterone oxide is obtained; taking the crude dihydrotestosterone oxide, adding solvent four, which is one or more of methanol, ethanol, acetone, isopropanol and other water-soluble solvents, and the weight ratio of the solvent four to the fine dihydrotestosterone mixture is 2-10:1; reflux time is 0.5-1h; then dripping 0.5-1.0 times the weight of drinking water in the solvent four under reflux state, keeping reflux for 0.5-1h after dripping, and then cooling and crystallizing, the crystallization temperature is 0-25℃, and the crystallization time is 0.5-3h; the drying temperature is: 60-90℃; after drying, the fine dihydrotestosterone oxide is obtained, and the purity is ≥98%.

4. A method for recycling a dihydrotestosterone mother liquor and an intermediate mother liquor thereof according to claim 3, characterized in that: The solvent five in the step C is one of methanol and ethanol, preferably ethanol; the weight ratio of the added amount to the dihydrotestosterone oxide product is 1-5:1; the catalyst is one or more of pyridine hydrochloride, p-toluenesulfonate, pyridine p-toluenesulfonate, etc., and the weight ratio of the added amount to the dihydrotestosterone oxide product is 0.1-1.0:1; the dehydrating agent is one of triethyl orthoformate and trimethyl orthoformate, and the weight ratio of the added amount to the dihydrotestosterone oxide product is 0.5-2.0:1; 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 obtained material is dihydrotestosterone etherified product with a purity of ≥98%.

5. A method for recycling a dihydrotestosterone mother liquor and an intermediate mother liquor thereof according to claim 1, 2 or 4, characterized in that: The solvent six in step D is one of methanol, ethanol, tetrahydrofuran, etc., and the weight ratio of the added amount to the dihydrotestosterone oxide product is 3-10:1; the reducing agent is one or more of potassium borohydride, sodium borohydride, sodium triacetoxyborohydride, etc., and the weight ratio of the added amount to the dihydrotestosterone oxide product is 0.1-0.5:1; the reaction temperature is between 0-40°C, and the reaction time is 1.0-5.0h; the method for terminating the reaction after the reaction is completed is to add drinking water, and the weight ratio of the water to the dihydrotestosterone oxide product is 0.5-1.5: 1; control the temperature to be 0-15°C; add one of hydrochloric acid and sulfuric acid as the acid, and the weight ratio of the added amount to the fine 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, add one or more of sodium hydroxide, sodium carbonate, and sodium bicarbonate as the alkali, and the weight ratio of the added amount to the fine 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 obtained material is a crude dihydrotestosterone product with a purity of ≥96%.

6. A method for recycling a dihydrotestosterone mother liquor and an intermediate mother liquor thereof according to claim 5, characterized in that: The solvent seven in the step E is one of methanol, ethanol, acetone and isopropanol, 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 seven; the temperature of cooling and crystallization is 0-10°C, and the crystallization time is 0.5-3h; and the dihydrotestosterone is refined to obtain a purity of ≥99%.

Images