Progesterone preparation composition and preparation method thereof
The production method of progesterone preparations using dry heat sterilization and specific compound ratios solves the problem of insufficient sterility of progesterone injections, achieving high efficiency in sterility and quality stability, and meeting regulatory requirements.
Patent Information
- Application Number
- CN202410778896.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-06-17
- Publication Date
- 2025-12-19
AI Technical Summary
The existing moist heat sterilization process for progesterone injections cannot meet current regulatory requirements, resulting in insufficient sterility. Therefore, it is necessary to develop a safe, effective, and robust production process.
The process employs dry heat sterilization combined with specific compound formulation and purification steps, including the preparation of ethers, nitro compounds, and progesterone. Through multi-step synthesis and purification, sterility is ensured by final dry heat terminal sterilization.
The progesterone injection solution achieves high sterility, meets regulatory requirements, ensures product quality stability and safety, and achieves a sterility assurance level (SAL) of <10⁻⁶ using a dry heat sterilization process.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of progesterone preparation composition, in particular to a kind of progesterone preparation composition and preparation method thereof. BACKGROUND
[0002] Progesterone is a human body endogenous progestogen, plays an important role in human fertility. It is widely used in clinical functional uterine bleeding, threatened abortion and habitual abortion, menorrhagia, dysmenorrhea, amenorrhea, endometriosis and advanced breast cancer, and is a kind of most basic progestogen drug.
[0003] In the late menstrual cycle, it can change the secretory phase of endometrium, provide favorable conditions for the implantation of zygote, reduce the excitability of pregnant uterus, and make the fetus grow safely. When acting with estrogen, it can promote breast development and prepare for lactation, inhibit the release of luteinizing hormone from anterior pituitary through negative feedback to hypothalamus, inhibit the development of follicle and ovulation process of ovary. Progesterone can be used for the treatment of menstrual disorders, functional uterine bleeding, luteal phase deficiency, threatened abortion and habitual abortion, and premenstrual tension syndrome.
[0004] Progesterone injection is an oily solution without water. The common moist heat sterilization process is not enough to provide sufficient sterile guarantee level, and dry heat sterilization process should be used. At present, domestic listed products generally use sterilization filtration, aseptic process or moist heat terminal sterilization process to ensure its sterility, which does not meet the requirements of current regulatory guidelines. Therefore, it is necessary to redevelop the prescription, production process and quality of progesterone injection, and establish a safe, effective and quality stable product. SUMMARY
[0005] In view of the above shortcomings of the prior art, the present application provides a kind of progesterone preparation composition and preparation method thereof, which can effectively solve the problems raised in the background art.
[0006] To achieve the above purpose, the technical scheme is as follows: The present application provides a kind of progesterone preparation composition, which comprises progesterone, and further comprises a first compound and a second compound, and the mass ratio of progesterone, the first compound and the second compound is 84.4:90:108.
[0007] Further, the progesterone is extracted from etherate and nitro compound, the first compound is prepared by dissolving, stirring 4AD extender, tetramethylpiperidine oxide and dichloromethane, adding sodium bromide, aqueous solution of sodium bicarbonate, and then adding sodium hypochlorite solution for extraction and concentration, and the second compound is prepared by dissolving the first compound with cyclohexene and acetonitrile, crystallizing and filtering.
[0008] A method for preparing a progesterone preparation composition, comprising the following steps: S1: Ether preparation, in a 1000ml three-necked flask, 100g 4AD, 200ml ethanol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, incubated at 20-25°C and stirred for 12-16 hours, TLC detection of reaction end point, after the reaction, 3ml pyridine was added, stirred for 20-25 minutes to neutralize the acid, then the system was cooled to -5-0°C, stirred for 2-3 hours, filtered, washed with a small amount of ethanol, the wash and filtrate were combined, the solvent was recovered and the crude product was reused; the filter cake was dried below 70°C, and 101.6g of ether was obtained; S2: Nitro compound preparation, in a 1000ml three-necked flask, 100g ether, 400ml nitroethane, 5ml ethylenediamine, incubated at 85-90°C and stirred for 6-8 hours, TLC detection of reaction end point, after the reaction, the nitromethane was recovered by vacuum concentration and reused. In the above residue, 800ml alcohol was added, heated to dissolve, 5g activated carbon was added, refluxed for 1-1.5 hours, filtered while hot, the filter cake was washed with about 80ml alcohol, the filtrate and wash were combined, concentrated under normal pressure to recover about 85% alcohol, then 500ml pure water was added, about 150ml solvent containing 50-60% ethanol was distilled out, the system was then cooled to 5-10°C, stirred for 2-3 hours to crystallize, filtered, the filter cake was washed with a small amount of 50% ethanol solution, and dried below 70°C, and 104.6g of nitro compound was obtained; S3: Progesterone preparation, in a 1000ml three-necked flask, 100g nitro compound, 500ml ethanol, 60g zinc powder was added at room temperature with stirring, slowly heated to 60-65°C, 240ml 30% hydrochloric acid solution was added dropwise, about 1.5-2 hours for dropwise addition, after dropwise addition, incubated for 4-5 hours, after the reaction, about 90-95% ethanol was recovered by vacuum distillation, then 600ml tap water was added, cooled to 10-15°C, stirred for 2-3 hours to crystallize, filtered, washed with water until neutral, the filter cake was dried below 70°C, and the progesterone crude product was obtained. The above progesterone crude product was dissolved in 600ml alcohol, 5g activated carbon was added, heated to reflux and decolorized for 1-1.5 hours, filtered while hot, the filter cake was washed with 100ml alcohol, the wash and filtrate were combined, concentrated under normal pressure to recover about 90% alcohol, then cooled to -5-0°C, frozen for 2-3 hours to crystallize, filtered, the filter cake was washed with a small amount of alcohol, and dried below 70°C, and 84.2g of progesterone was obtained; S4: Synthesis of No. 1 compound, 100 g of 4AD derivative in a 2L single-neck flask, tetramethylpiperidine oxide, 3V dichloromethane was added and dissolved, stirred, added sodium bromide, aqueous sodium bicarbonate solution, then added 10V sodium hypochlorite solution, stirred at 25°C for 16-20h, TLC detection until the raw material was completely reacted, separated, extracted with 300ml dichloromethane twice, combined the organic phase, washed with water once, concentrated to dryness, methanol entrainment twice, then added 10V methanol, concentrated to 3-5V volume, stirred, added 7V water dropwise, filtered, dried at 50°C, obtained 90g of compound 2; S5: Synthesis of No. 2 compound, under nitrogen protection: 1-cyclohexene was added to 2V acetonitrile, heated to 65-68°C to dissolve, then compound 2 was added, stirred until clear, cooled to 42°C, stirred for 10-16h, placed in the laboratory refrigerator, cooled to -20°C, crystallized for 2h, filtered, then washed with 2V cold acetonitrile at -5°C-0°C once, stirred for 2h, filtered, naturally air-dried to obtain 108g of compound 3; S6: Synthesis of progesterone, under nitrogen protection, 5g cuprous chloride was added to a three-neck flask, 500ml DMF, heated to 65°C to dissolve, stirred for 1h for standby, under nitrogen protection, compound 3 was added to a three-neck flask, dichloromethane was stirred to dissolve, cooled to -20°C, poured into the above prepared cuprous chloride DMF solution, air was passed, maintained at 5-8°C, stirred for 16-24h, TLC detection until the raw material was less than 1%, cooled to 0-5°C, added 10% dilute sulfuric acid solution 200ml, stirred for 30min, added 300ml dichloromethane and 300ml water, stirred for 15min, then separated, the aqueous phase was extracted with 200ml dichloromethane once, the dichloromethane was combined and concentrated to about 1 volume, 200ml methanol was replaced twice, concentrated to about 1.5 volumes, then 5V water was added dropwise at room temperature, refrigerated for 1-2h, filtered, washed with cold methanol solution, dried at 55°C to obtain 85g of crude progesterone; S7: Purification of progesterone, in the reaction bottle, dichloromethane was added, crude progesterone was added, 5V sodium hypochlorite was added, stirred, until HPLC detection of compound 2 and compound 3 was less than 0.1%, separated, extracted with dichloromethane twice, 100ml each time, washed with 10% sodium thiosulfate 200ml once, washed with saturated brine 200ml once, added activated carbon, heated to 35°C, stirred for 1h, filtered into a clean area, concentrated, then replaced with methanol twice, about 2V methanol each time, controlled at 50°C, concentrated to a sticky state, cooled to crystallize for 1h, filtered, the filter cake was washed with a small amount of methanol, dried, washed with water, dried, the filter cake was dried at 50-60°C for 12h, sampled and detected, qualified, then loaded, yield 80%.
[0009] S8: Progesterone filling, progesterone injection is a high viscosity liquid within 20-60℃, the standard volume of 0.8ml:20mg progesterone injection is 0.94ml, the standard volume of 1ml:25mg progesterone injection is 1.15ml, and the standard volume of 1ml:10mg progesterone injection is 1.15ml; S9: Progesterone sterilization, including two-stage 0.22mm sterilization filtration, aseptic filling technology and terminal sterilization process, using dry heat terminal sterilization process of overkill method, the stirring dissolution temperature in commercial production equipment is above room temperature, and the dissolution time is not less than 60 minutes to ensure that the raw material is completely dissolved, the standard dry heat sterilization condition is >160℃x>120min, and other temperature and time combinations equivalent to the standard sterilization condition can also be used.
[0010] Compared with the known prior art, the technical scheme provided by the present application has the following beneficial effects: In view of the prescription of the non-aqueous solvent system, the dry heat sterilization process should be preferred to the moist heat sterilization process to ensure the sterility of the product, and the dry heat sterilization process of >170°C / 60min is designed in the development process of the product, the sterilization condition meets the overkill condition, and the performance of the dry heat sterilization equipment has been confirmed in empty and full load performance, so it is considered that the expected sterility assurance level SAL<10-6 can be achieved. BRIEF DESCRIPTION OF DRAWINGS
[0011] In order to more clearly illustrate the technical scheme in the embodiments of the present application or the prior art, the drawings needed in the following embodiment or prior art description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and those skilled in the art can obtain other drawings according to these drawings without creative labor.
[0012] Figure 1 The figure is a process flow diagram of the present application. DETAILED DESCRIPTION
[0013] In order to make the purpose, technical scheme and advantages of the embodiments of the present application more clear, the technical scheme in the embodiments of the present application will be clearly and completely described below in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.
[0014] The present application will be further described below in combination with the embodiments.
[0015] Embodiment 1 For the first embodiment of the present application, a progesterone preparation composition comprises progesterone, and further comprises: a first compound and a second compound, the mass ratio of progesterone, the first compound and the second compound being 84.4:90:108, the progesterone being extracted from etherate and nitro compound, the first compound being prepared by dissolving, stirring 4AD extender, tetramethylpiperidine oxide and dichloromethane, adding sodium bromide, aqueous solution of sodium bicarbonate, and then adding solution of sodium hypochlorite for extraction and concentration, and the second compound being prepared by dissolving the first compound, cyclohexene and acetonitrile and then filtering after crystallization.
[0016] Embodiment 2 Reference Figure 1 For the second embodiment of the present application, the difference between the second embodiment and the first embodiment is that: a preparation method of a progesterone preparation composition comprises the following steps: S1: etherate preparation, in a 1000ml three-necked flask, 100g of 4AD, 200ml of ethanol, 80ml of triethyl orthoformate, and 2g of p-toluenesulfonic acid are added, and the system is stirred and reacted at 20-25℃ for 12-16 hours, the reaction end point is detected by TLC, after the reaction is completed, 3ml of pyridine is added, the acid is neutralized by stirring for 20-25 minutes, then the system is cooled to-5-0℃, and the system is stirred and crystallized for 2-3 hours, and then the system is filtered, washed with a small amount of ethanol, and the washing liquid and the filtrate are combined, and the solvent and the crude product are recovered for reuse; the filter cake is dried at below 70℃, and 101.6g of etherate is obtained, with an HPLC content of 99.2% and a weight yield of 101.6%; S2: nitro compound preparation, in a 1000ml three-necked flask, 100g of etherate, 400ml of nitroethane, and 5ml of ethylenediamine are added, and the system is stirred and reacted at 85-90℃ for 6-8 hours, the reaction end point is detected by TLC, after the reaction is completed, the system is concentrated under reduced pressure, and the nitromethane is recovered for reuse. In the above residue, 800ml of alcohol is added, and the system is heated to dissolve, 5g of activated carbon is added, and the system is refluxed and decolorized for 1-1.5 hours, and then the system is filtered while hot, the filter cake is washed with about 80ml of alcohol, the filtrate and the washing liquid are combined, the system is concentrated under normal pressure until about 85% of the alcohol is recovered, then 500ml of pure water is added, the system is continuously evaporated until about 150ml of solvent containing 50-60% of ethanol is evaporated, then the system is cooled to 5-10℃, and the system is stirred and crystallized for 2-3 hours, and then the system is filtered, the filter cake is washed with a small amount of 50% ethanol solution, and the filter cake is dried at below 70℃, and 104.6g of nitro compound is obtained, with an HPLC content of 99.2% and a total weight yield of 104.6%; S3: Preparation of progesterone, in a 1000 ml three-necked flask, 100 g of nitro compound, 500 ml of ethanol, under stirring at room temperature, 60 g of zinc powder was added, slowly heated to 60-65 °C, 240 ml of 30% hydrochloric acid solution was added dropwise, about 1.5-2 hours dropwise, after dropwise addition, the reaction was kept for 4-5 hours, after the reaction was completed, about 90-95% of ethanol was recovered by distillation under reduced pressure, then 600 ml of tap water was added, cooled to 10-15 °C, stirred for 2-3 hours, filtered, washed with water until neutral, the filter cake was dried below 70 °C, to obtain crude progesterone. The above-mentioned crude progesterone was dissolved in 600 ml of alcohol, 5 g of activated carbon was added, heated to reflux for 1-1.5 hours, filtered while hot, 100 ml of alcohol was used to wash the filter cake, the wash and filtrate were combined, concentrated under normal pressure to recover about 90% of alcohol, then cooled to -5-0 °C, frozen to crystallize for 2-3 hours, filtered, the filter cake was washed with a small amount of alcohol, dried below 70 °C, to obtain 84.2 g of progesterone with a melting point of 129.5-130.5 °C, HPLC content of 99.7%, yield of 84.2%, the mother liquor was recovered and the crude product was reused; S4: Synthesis of No. 1 compound, 100 g of 4AD derivative in a 2L single-necked flask, tetramethylpiperidine oxide was added, dissolved in 3V dichloromethane, stirred, added sodium bromide, aqueous sodium bicarbonate solution, then added 10V sodium hypochlorite solution, stirred at 25 °C for 16-20 h, TLC detection until the raw material was completely reacted, separated, extracted with 300 ml of dichloromethane twice, combined the organic phase, washed with water once, concentrated to dryness, methanol was added twice, then added 10V of methanol, concentrated to 3-5V volume, added 7V of water dropwise under stirring, filtered, dried at 50 °C, to obtain 90 g of compound 2 with HPLC > 98; S5: Synthesis of No. 2 compound, under nitrogen protection: 1-cyclohexene was added to 2V of acetonitrile, heated to 65-68 °C to dissolve, then compound 2 was added, stirred until clear, cooled to 42 °C, stirred for 10-16 h, placed in the laboratory refrigerator, cooled to -20 °C, crystallized for 2 h, filtered, then washed with 2V of cold acetonitrile at -5-0 °C for 1 time, stirred for 2 h, filtered, naturally air-dried to obtain 108 g of compound 3; S6: Progesterone synthesis, under nitrogen protection, in a three-necked flask, add 5g cuprous chloride, 500ml DMF, heat to 65 degrees to dissolve, stir for 1h, wait for use, under nitrogen protection, in a three-necked flask, add compound 3, dichloromethane, stir to dissolve, cool to minus 20 degrees, pour into the above prepared cuprous chloride DMF solution, pass air, maintain stable at 5-8 degrees, stir for 16-24h, TLC detection to less than 1% of the remaining raw material, cool to 0-5 degrees, add 10% dilute sulfuric acid solution 200ml, stir for 30 minutes, add 300ml dichloromethane and 300ml water, stir for 15 minutes and separate, the aqueous phase is extracted once with 200ml dichloromethane, combine dichloromethane and concentrate to about 1 volume of the system, replace with 200ml methanol twice, concentrate to about 1.5 volumes of the system, then add 5V water dropwise at room temperature, freeze in the refrigerator for 1-2 hours, filter, rinse with cold methanol solution, dry the material at 55 degrees, to get 85g of progesterone crude product; S7: Progesterone impurity removal and purification, in the reaction flask, add dichloromethane, progesterone crude product, add 5V sodium hypochlorite, stir, until HPLC detection of compound 2, compound 3 is less than 0.1%, separate, dichloromethane extraction twice, each 100ml, 10% sodium thiosulfate 200ml washing once, saturated brine 200ml washing once, add activated carbon, heat to 35 degrees, stir to decolorize for 1 hour, filter the system into a clean area reaction concentrate, later use methanol twice, each use about 2V methanol, control temperature 50 degrees, concentrate to sticky, cool to precipitate for 1 hour, filter, filter cake with a small amount of methanol rinse, dry, water wash, dry, filter cake at 50-60 degrees dry for 12 hours, take sample detection, qualified, load, yield 80%.
[0017] S8: Progesterone filling, progesterone injection is a high viscosity liquid at 20-60 degrees, the standard filling amount of 0.8ml:20mg specification progesterone injection is 0.94ml, the standard filling amount of 1ml:25mg specification progesterone injection is 1.15ml, the standard filling amount of 1ml:10mg specification progesterone injection is 1.15ml, the minimum filling amount of 0.8ml:20mg, 1ml:25mg and 1ml:10mg specification progesterone injection is 0.88ml, 1.10ml, 1.10ml respectively, which is lower than the standard filling amount value recommended by Chinese Pharmacopoeia, therefore, the standard filling amount recommended by Chinese Pharmacopoeia can be used as the target value, the acceptable minimum filling amount obtained by test can be used as the lower limit, combined with the performance of commercial filling equipment, the filling amount range of the product to be developed is determined: 1ml:10mg specification:1.10ml~1.20ml(1.01g~1.10g) 0.8ml:20mg specification:0.88ml~1.00ml(0.83g~0.94g) 1ml:25mg; Specifications: 1.10ml~1.20ml (1.04g~1.13g); S9: Progesterone sterilization, including two-stage 0.22mm sterilization filtration, aseptic filling technology and terminal sterilization process. It adopts the dry heat terminal sterilization process of overkill method. In commercial production equipment, the stirring and dissolution temperature is above room temperature and the dissolution time is not less than 60 minutes to ensure complete dissolution of the raw drug. The standard dry heat sterilization conditions are >160℃ x >120min. Other temperature and time combinations equivalent to the standard sterilization conditions can also be used. To meet the requirements of dry heat terminal sterilization and commercial production scale of progesterone injection, a dry heat sterilizer was specially designed and manufactured during the product development process. The following are some of the key performance requirements of the dry heat sterilizer. 1. Internal cavity volume: 2000L or more; 2. Settable temperature range: 30~200℃ (or 5℃ higher than ambient temperature); 3. The room temperature should not rise to 170℃ under no-load conditions for more than 60 minutes; 4. When sterilizing at 170℃ or above under no-load conditions, the temperature deviation at multiple points should not exceed 10℃; 5. The room temperature should not rise to 170℃ under full load for more than 120 minutes; 6. When sterilizing at full load above 170℃, the temperature deviation at multiple points should not exceed 15℃; When confirming the dry heat sterilization procedure for progesterone injection, it is necessary to assess the impact of the high-temperature heat treatment process on the physicochemical properties of the product. To this end, a simulation test was designed based on the temperature change when the dry heat sterilizer was running at >170℃ for 60 min under full load conditions. The test evaluated the differences in the physicochemical properties of the product at the hot and cold points of the equipment, as well as the quality level of the product under extreme temperatures. During the test, the quality attributes of progesterone injection that are closely related to high temperature did not change significantly or adversely. Based on this, it is believed that the three specifications of progesterone injection can withstand the actual sterilization temperature and time produced by commercial dry heat sterilizers at 2170℃ for 60 min.
[0018] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions will not cause the essence of the corresponding technical solutions to deviate from the protection scope of the technical solutions of the embodiments of the present invention.
Claims
1. A progesterone preparation composition, characterized in that, It includes progesterone, and also includes compound one and compound two, wherein the mass ratio of progesterone, compound one and compound two is 84.4:90:
108.
2. The progesterone preparation composition according to claim 1, characterized in that, The progesterone is derived from ethers and nitro compounds. The first compound is prepared by dissolving and stirring the first compound with 4AD extension, tetramethylpiperidine oxide and dichloromethane, adding an aqueous solution of sodium bromide and sodium bicarbonate, and then adding a solution of sodium hypochlorite for extraction and concentration. The second compound is prepared by dissolving the first compound with cyclohexene and acetonitrile, followed by crystallization and filtration.
3. A method for preparing a progesterone formulation composition, comprising a progesterone formulation composition as described in claim 2, characterized in that, Includes the following steps: S1: Preparation of the ether compound: In a 1000ml three-necked flask, add 100g of 4AD, 200ml of ethanol, 80ml of triethyl orthoformate, and 2g of p-toluenesulfonic acid. Incubate at 20-25℃ and stir for 12-16 hours. Detect the reaction endpoint by TLC. After the reaction is complete, add 3ml of pyridine and stir for 20-25 minutes to neutralize the acid. Then cool the system to -5 to 0℃ and stir to crystallize for 2-3 hours. Filter, wash with a small amount of ethanol, combine the washings and filtrate, and reuse the recovered solvent and crude product. Dry the filter cake below 70℃ to obtain 101.6g of the ether compound. S2: Preparation of the nitro compound: In a 1000ml three-necked flask, add 100g of ether, 400ml of nitroethane, and 5ml of ethylenediamine. Maintain the temperature at 85-90℃ and stir for 6-8 hours. Detect the reaction endpoint by TLC. After the reaction is complete, concentrate under reduced pressure and recover the nitromethane for reuse. Add 800ml of ethanol to the above residue, heat to dissolve, add 5g of activated carbon, reflux for decolorization for 1-1.5 hours, filter while hot, wash the filter cake with about 80ml of ethanol, combine the filtrate and washings, concentrate under normal pressure to recover about 85% ethanol, then add 500ml of purified water, continue to distill off about 150ml of solvent containing 50-60% ethanol, then cool the system to 5-10℃, stir to crystallize for 2-3 hours, filter, wash the filter cake with a small amount of 50% ethanol solution, and dry below 70℃ to obtain 104.6g of the nitro compound. S3: Progesterone preparation: In a 1000ml three-necked flask, add 100g of nitro compound and 500ml of ethanol. While stirring at room temperature, add 60g of zinc powder. Slowly heat to 60-65℃, and dropwise add 240ml of 30% hydrochloric acid solution, approximately 1.5-100ml. The reaction was completed in 2 hours. After the addition was complete, the mixture was kept at a constant temperature for 4-5 hours. After the reaction was complete, the mixture was distilled under reduced pressure to recover about 90-95% of the ethanol. Then, 600 ml of tap water was added, the temperature was lowered to 10-15°C, and the mixture was stirred to crystallize for 2-3 hours. The mixture was then filtered, washed with water until neutral, and the filter cake was dried below 70°C to obtain crude progesterone. The crude progesterone was dissolved in 600 ml of alcohol, 5 g of activated carbon was added, and the mixture was heated and refluxed for decolorization for 1-1.5 hours. The mixture was filtered while hot, and the filter cake was washed with 100 ml of alcohol. The washing liquid and filtrate were combined and concentrated under normal pressure to recover about 90% of the alcohol. The mixture was then cooled to -5 to 0°C, and the mixture was frozen to crystallize for 2-3 hours. The mixture was then filtered, the filter cake was washed with a small amount of alcohol, and dried below 70°C to obtain 84.2 g of progesterone. S4: Synthesis of compound 1: 100g of 4AD derivative, tetramethylpiperidine oxide, was dissolved in 3V dichloromethane in a 2L single-necked flask. After stirring, an aqueous solution of sodium bromide and sodium bicarbonate was added, followed by a 10V sodium hypochlorite solution. The mixture was stirred at 25°C for 16-20h. TLC was used to monitor the reaction until the starting material was completely reacted. The mixture was separated, extracted twice with 300ml dichloromethane, and the organic phases were combined. The mixture was washed once with water and concentrated to dryness. Methanol was carried over twice, and 10V methanol was added. The mixture was concentrated to 3-5V volume, stirred, and 7V water was added dropwise. The mixture was filtered and dried at 50°C to obtain 90g of compound 2. S5: Synthesis of compound 2: Under nitrogen protection: 1-cyclohexene was added to 2V of acetonitrile, heated to 65-68℃ to dissolve, then compound 2 was added, stirred until clear, cooled to 42℃, stirred for 10-16h, placed in a laboratory refrigerator, cooled to -20℃, crystallized for 2h, filtered, then slurried once with 2V of cold acetonitrile at -5℃-0℃, stirred for 2h, filtered, and naturally dried to obtain 108g of compound 3; S6: Progesterone synthesis. Under nitrogen protection, add 5g cuprous chloride and 500ml DMF to a three-necked flask, heat to 65°C to dissolve, stir for 1 hour, and set aside. Under nitrogen protection, add compound 3 and dichloromethane to the three-necked flask, stir to dissolve, cool to -20°C, pour in the prepared cuprous chloride DMF solution, purge with air, maintain stable temperature at 5-8°C, stir for 16-24 hours, and monitor with TLC until the remaining raw material is below 1%. Cool to 0-5°C and add 1... 200 ml of 0% dilute sulfuric acid solution was stirred for 30 minutes. Then, 300 ml of dichloromethane and 300 ml of water were added and stirred for 15 minutes. The aqueous phase was separated and extracted once with 200 ml of dichloromethane. The dichloromethane was combined and concentrated until about 1 volume remained in the system. The system was replaced twice with 200 ml of methanol and concentrated until about 1.5 volume remained in the system. 5% water was added dropwise at room temperature. The system was frozen for 1-2 hours, filtered, washed with cold methanol solution, and dried at 55°C to obtain 85 g of crude progesterone. S7: Progesterone purification: In a reaction flask, add dichloromethane, crude progesterone, and 5V sodium hypochlorite. Stir until HPLC analysis shows that compounds 2 and 3 are less than 0.1%. Separate the mixture and extract twice with 100ml of dichloromethane each time. Wash once with 200ml of 10% sodium thiosulfate and once with 200ml of saturated brine. Add activated carbon, heat to 35°C, and stir for decolorization for 1 hour. Filter the system into a clean area for reaction concentration. Later, use methanol twice, about 2V of methanol each time, and control the temperature at 50°C. Concentrate to a viscous state, cool to crystallize for 1 hour, filter, rinse the filter cake with a small amount of methanol, dry under vacuum, wash with water, dry under vacuum, and dry the filter cake at 50-60°C for 12 hours. Take a sample for testing. If it passes the test, load the product. The yield is 80%. 4.S8: Progesterone filling. Progesterone injection is a high-viscosity liquid within the temperature range of 20℃-60℃. Therefore, the progesterone preparation composition made by aseptic filling process is divided into the following three specifications: 0.8ml:20mg progesterone injection with a standard filling volume of 0.94ml, 1ml:25mg progesterone injection with a standard filling volume of 1.15ml, and 1ml:10mg progesterone injection with a standard filling volume of 1.15ml. S9: Progesterone sterilization, including two-stage 0.22mm sterilization filtration, aseptic filling technology and terminal sterilization process. It adopts the dry heat terminal sterilization process of overkill method. In commercial production equipment, the stirring and dissolution temperature is above room temperature and the dissolution time is not less than 60 minutes to ensure complete dissolution of the raw drug. The standard dry heat sterilization conditions are >160℃ x >120min. Other temperature and time combinations equivalent to the standard sterilization conditions can also be used.