Preparation method of didrogesterone
By using a combination of methanesulfonic acid catalyst and photocatalyst BHT, along with specific solvents and reaction conditions, the problems of insufficient purity and yield in the synthesis of dydrogesterone were solved, and the industrial production of high-purity, high-yield dydrogesterone was realized.
Patent Information
- Application Number
- CN202511996675.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-27
- Publication Date
- 2026-02-13
AI Technical Summary
The existing synthesis process for dydrogesterone suffers from insufficient purity and yield.
Using methanesulfonic acid as a catalyst, N-bromosuccinimide is used for bromination. Combined with a photocatalyst and polymerization inhibitor BHT, dydrogesterone is synthesized through steps of ketalization, halogenation, elimination, photoreaction, deprotection, and isomerization. The reaction conditions are controlled, and specific solvents and catalysts are used.
It improves the purity and yield of dydrogesterone, reduces the generation of byproducts, and is suitable for large-scale industrial production.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the production process of steroid drugs, in particular to a synthetic method of dydrogesterone. BACKGROUND
[0002] Dydrogesterone, CAS No. 152-62-5. It is an oral progestogen that can make the endometrium into a complete secretory phase, thereby preventing the risk of endometrial hyperplasia and cancer caused by estrogen.
[0003] At present, it is urgent to develop a new synthetic process of dydrogesterone. SUMMARY
[0004] In view of the defects of the prior art, the purpose of the present application is to provide a synthetic process of dydrogesterone with high purity and high yield.
[0005] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows: The present application provides a synthetic process of dydrogesterone, specifically Step one is ketalization, and progesterone is reacted in an organic solvent with methylsulfonic acid as a catalyst, Step two is halogenation, and under anhydrous and anaerobic conditions, N-bromosuccinimide and a free radical initiator are added to the organic solvent to carry out bromination reaction; Step three is elimination reaction, which is a reaction under alkaline conditions; Step four is photoreaction, which is carried out under inert gas conditions by adding a photocatalyst, a polymerization inhibitor and a solvent at-20~30℃; Step five is deprotection, which is carried out under acidic conditions; Step six is isomerization, which is carried out under acidic conditions to obtain dydrogesterone product.
[0006] Compared with the prior art, the present application has the following beneficial effects: The present application uses methylsulfonic acid as a catalyst, which not only has high catalytic efficiency, but also avoids aromatic by-product pollution due to the absence of benzene ring in the molecular structure, and is easy to separate and remove impurities.
[0007] BHT is used as a polymerization inhibitor to effectively prevent the occurrence of side reactions.
[0008] The present application has mild reaction conditions, high yield and ultra-low residual content of by-products, and is suitable for large-scale manufacturing application of drug synthesis. DETAILED DESCRIPTION
[0009] Following, the advantages and effects of the present application can be easily understood by those skilled in the art from the disclosure of the present specification. The present application can also be implemented or applied by other different embodiments, and the details in the present specification can be modified or changed based on different views and applications without departing from the spirit of the present application.
[0010] Furthermore, it should be understood that the one or more method steps mentioned in the present application do not exclude that other method steps can exist before and after the mentioned combination steps or other method steps can be inserted between the explicitly mentioned steps, unless otherwise specified; and, unless otherwise specified, the numbering of the method steps is only a convenient tool to identify the method steps and is not intended to limit the arrangement order of the method steps or to limit the scope of the present application, and the change or adjustment of the relative relationship without substantial change of the technical content is also considered as the scope of the present application.
[0011] The present application provides a preparation method of dydrogesterone, which is prepared from progesterone by the following steps, Step one is ketalization, progesterone is reacted in an organic solvent with methylsulfonic acid as catalyst, the reaction temperature is 20-50℃; the organic solvent can be selected from one or more of petroleum ether, n-hexane, n-heptane, isooctane, dichloromethane, dichloroethane, trichloromethane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, butyl acetate; Step two is halogenation, under anhydrous and anaerobic conditions, N-bromosuccinimide is added in an organic solvent, then a free radical initiator benzoyl peroxide or azobisisobutyronitrile is added, and the bromination reaction is carried out by heating to 30-80℃; the solvent is selected from one or more of carbon tetrachloride, chloroform, acetonitrile; the post-treatment is through alkali washing, such as 5% NaOH solution, and then distillation, column chromatography or crystallization to separate the target product; Step three is elimination reaction, which is carried out under basic conditions; the base is selected from inorganic bases such as sodium hydroxide and potassium hydroxide, and the solvent is selected from alcohol solvents such as ethanol, propanol and isopropanol; Step four is photoreaction, under inert gas conditions, a photo catalyst, a polymerization inhibitor and a solvent are added, and the reaction is carried out at -20-30℃; the photoreaction uses LED ultraviolet light with a wavelength range of 265-365nm, the first stage uses light with a wavelength of 265-300nm, and the second stage uses light with a wavelength of 305-365nm; the light irradiation time of the photoreaction is selected as 10-50 hours; the photo catalyst is selected from anthraquinone catalysts; the solvent is selected from anhydrous solvents such as anhydrous acetonitrile and anhydrous DMF; the polymerization inhibitor is selected from BHT (dibutylhydroxytoluene); the inert gas is, for example, nitrogen or argon; Step five is deprotection, deprotection under acidic conditions, for example using hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, preferably methanesulfonic acid; the solvent is selected from ethyl acetate, ethanol and the like; the temperature is 70-90 degrees Celsius; Step six is isomerization, the catalyst is Lewis acid, for example zinc chloride; the solvent is for example DMF, DMSO, acetonitrile and the like; the temperature is 20-50 degrees Celsius; the post-treatment is neutralized with inorganic base; to obtain the product of medroxyprogesterone.
[0012] The synthetic route of medroxyprogesterone is as follows: Synthetic example 1 Take 1 kg of progesterone and add it to a 20 L reaction tank, then add 500 g of ethylene glycol, 2 L of ethyl acetate, slowly add 900 g of methanesulfonic acid, control the temperature at 35°C, react for 3 hours, then cool at 0°C, wash with 5 L of water, 2 L of acetone, dry, and vacuum dry at 40°C to obtain the crude product. Put the crude product into a 20 L reaction tank, add 6 L of acetone, 500 mL of ethanol, heat to reflux in a water bath, stir for 1 hour, cool at 0°C, filter, and vacuum dry at 40°C overnight to obtain the pure product of compound 2, with a yield of 94%.
[0013] Take 1 kg of compound 2 and add it to a 50 L reaction tank, add 20 L of acetonitrile, protect with nitrogen, add 5 g of azobisisobutyronitrile (AIBN), then add 150 mL of DBU, heat to 65°C, slowly add 500 g of bromosuccinimide, react for 2 h, filter, dissolve the solid in DCM, wash with saturated sodium bicarbonate solution, dry, and evaporate the filtrate under reduced pressure to obtain compound 3, with a yield of 89%.
[0014] Take 1 kg of compound 3 and add it to a 20 L reaction tank, add 120 g of sodium hydroxide and 5 L of ethanol, protect with nitrogen, heat to 120°C, react for 2 h, then add 5 L of acetonitrile / ethanol=1 / 1 by volume, recrystallize, filter, dry, and dry at 40°C overnight to obtain compound 4, with a yield of 91%.
[0015] Take 1 kg of compound 4 and add it to a 50 L reaction tank, add 20 L of anhydrous acetonitrile, 1.2 g of 1,8-dihydroxyanthraquinone, and 1 g of polymerization inhibitor BHT, protect with nitrogen, the wavelength of photochemical ring-opening reaction is 275 nanometers, the reaction temperature is 0°C, the reaction time is 15 hours, the wavelength of photochemical ring-closing reaction is 335 nanometers, the reaction temperature is controlled at 0°C, and the reaction time is 15 hours. Remove the solvent under reduced pressure, then add 20 mL of a mixture of anhydrous DMF / anhydrous acetonitrile=2 / 1 by volume, heat to reflux for 30 minutes, cool at 0°C, filter, and recrystallize with isopropyl alcohol to obtain compound 5, with a yield of 88%.
[0016] The above compound 5 was dissolved in ethyl acetate, 300 g of methanesulfonic acid was added, and the reaction was carried out at 80°C. After the reaction was completed, the solvent was removed under reduced pressure, extracted with DCM, washed with sodium bicarbonate solution until neutral, dried, and the solvent was recovered by distillation under reduced pressure, and then recrystallized with ethanol to obtain compound 6 by suction filtration.
[0017] A solution of 400 g of zinc chloride in 20 L of acetonitrile was added to a reaction tank containing the above compound 6, and the reaction was stirred at 25°C. After that, it was neutralized with sodium bicarbonate, extracted with DCM, washed with acetonitrile, and dried to obtain compound 7, which is medroxyprogesterone, at a yield of 86% and a purity of 99.9%.
[0018] Synthesis Example 2 1 kg of progesterone was weighed and added to a 20 L reaction tank, and then 500 g of ethylene glycol, 2 L of ethyl acetate, and 900 g of methanesulfonic acid were sequentially added while slowly dropping. The temperature was controlled at 35°C, and the reaction was carried out for 3 hours. After that, it was cooled at 0°C, washed with 5 L of water and 2 L of acetone, and dried under vacuum at 40°C or lower to obtain a crude product. The crude product was put into a 20 L reaction tank, 6 L of acetone and 500 mL of ethanol were added, and heated to reflux in a water bath while stirring for 1 hour. After that, it was cooled at 0°C, suction filtered, and dried under vacuum at 40°C overnight to obtain a pure compound 2 at a yield of 94%.
[0019] 1 kg of compound 2 was weighed and added to a 50 L reaction tank, 20 L of acetonitrile was added, and then 5 g of azobisisobutyronitrile (AIBN), 150 mL of DBU, and 500 g of bromosuccinimide were sequentially added while slowly dropping. The reaction was carried out for 2 hours. After that, it was suction filtered, the solid was dissolved in DCM, washed with saturated sodium bicarbonate solution, dried, and the filtrate was evaporated under reduced pressure to obtain compound 3 at a yield of 89%.
[0020] 1 kg of compound 3 was weighed and added to a 20 L reaction tank, 120 g of sodium hydroxide and 5 L of ethanol were added, and then heated to 120°C under nitrogen atmosphere. After that, 5 L of acetonitrile / ethanol=volume ratio 1 / 1 was added, recrystallized, filtered, suction dried, and dried at 40°C overnight to obtain compound 4 at a yield of 91%.
[0021] 1 kg of compound 4 was weighed and added to a 50 L reaction tank, 20 L of anhydrous acetonitrile, 1.2 g of 1,8-dihydroxyanthraquinone, and 1 g of a polymerization inhibitor BHT were added, and then photochemical ring-opening reaction was carried out at a wavelength of 275 nm at 0°C for 15 hours. Photochemical ring-closing reaction was carried out at a wavelength of 335 nm at 0°C for 15 hours. After that, 20 mL of a mixed solvent of anhydrous DMF / anhydrous acetonitrile=volume ratio 2 / 1 was added, heated to reflux for 30 minutes, cooled at 0°C, suction filtered, and recrystallized with isopropyl alcohol to obtain compound 5 at a yield of 88%.
[0022] The above compound 5 was dissolved in ethyl acetate, 100 g of hydrochloric acid was added, and the reaction was carried out at 80°C. After the reaction was completed, the solvent was removed under reduced pressure, extracted with DCM, washed with sodium bicarbonate solution until neutral, dried, and the solvent was recovered by distillation under reduced pressure. Then, recrystallization was performed using ethanol, and compound 6 was obtained by suction filtration.
[0023] A solution of 400 g of zinc chloride in 20 L of acetonitrile was added to a reaction tank containing the above compound 6, and the reaction was stirred at 25°C. Then, sodium bicarbonate was added for neutralization, extracted with DCM, washed with acetonitrile, and dried to obtain compound 7, medroxyprogesterone, at a yield of 80% and a purity of 99.8%.
[0024] Comparative Example 1 1 kg of progesterone was weighed and added to a 20 L reaction tank. Then, 500 g of ethylene glycol and 2 L of ethyl acetate were sequentially added, and 900 g of methanesulfonic acid was slowly added dropwise while controlling the temperature at 35°C. After 3 hours of reaction, the reaction was cooled at 0°C, and then washed with 5 L of water and 2 L of acetone, and dried under vacuum at 40°C or lower to obtain a crude product. The crude product was put into a 20 L reaction tank, 6 L of acetone and 500 mL of ethanol were added, and heated to reflux in a water bath for 1 hour. Then, the reaction was cooled at 0°C, suction filtered, and dried under vacuum at 40°C overnight to obtain a pure compound 2 at a yield of 94%.
[0025] 1 kg of compound 2 was weighed and added to a 50 L reaction tank. Then, 20 L of acetonitrile was added, and the reaction was protected by nitrogen. Then, 5 g of azobisisobutyronitrile (AIBN) was added, followed by the addition of 150 mL of DBU. The reaction was heated to 65°C, and 500 g of bromosuccinimide was slowly added dropwise. After 2 hours of reaction, the solid was dissolved in DCM, washed with saturated sodium bicarbonate solution, dried, and the filtrate was evaporated under reduced pressure to obtain compound 3 at a yield of 89%.
[0026] 1 kg of compound 3 was weighed and added to a 20 L reaction tank. Then, 120 g of sodium hydroxide and 5 L of ethanol were added, and the reaction was heated to 120°C under nitrogen protection. After 2 hours of reaction, 5 L of acetonitrile / ethanol (1 / 1 by volume) was added, and recrystallization was performed. Then, the reaction was filtered, dried, and dried under vacuum at 40°C overnight to obtain compound 4 at a yield of 91%.
[0027] 1 kg of compound 4 was weighed and added to a 50 L reaction tank. Then, 20 L of anhydrous acetonitrile, 1.2 g of 1,8-dihydroxyanthraquinone, and 0.5 g of a polymerization inhibitor, hydroquinone, were added, and the reaction was protected by nitrogen. Then, photochemical ring-opening reaction was performed at a wavelength of 275 nm at 0°C for 15 hours. Photochemical ring-closing reaction was performed at a wavelength of 335 nm at 0°C for 15 hours. Then, the solvent was removed under reduced pressure, and 20 mL of a mixed solvent of ethanol / acetonitrile (2 / 1 by volume) was added. The reaction was heated to reflux for 30 minutes, cooled at 0°C, suction filtered, and recrystallized using isopropyl alcohol to obtain compound 5 at a yield of 76%.
[0028] Compound 5 was dissolved in ethyl acetate, 100 g of hydrochloric acid was added, and the reaction was carried out at 80 °C. After the reaction was completed, the solvent was removed under reduced pressure, extracted with DCM, washed with sodium bicarbonate solution until neutral, dried, and the solvent was recovered by distillation under reduced pressure. The mixture was then recrystallized with ethanol and filtered to obtain compound 6.
[0029] A solution of 400g zinc chloride in 20L acetonitrile was added to the reaction vessel containing compound 6. The mixture was stirred at 25°C, then neutralized with sodium bicarbonate, extracted with DCM, washed with acetonitrile, and dried to obtain compound 7, dydrogesterone, with a yield of 76% and a purity of 99.4%.
[0030] Comparative Example 2 1 kg of progesterone was weighed and added to a 20 L reaction vessel, followed by 500 g of ethylene glycol and 2 L of ethyl acetate. 1600 g of p-toluenesulfonic acid was slowly added dropwise. The temperature was controlled at 35 °C, and the reaction was carried out for 3 hours. The mixture was then cooled to 0 °C and washed successively with 5 L of water and 2 L of acetone. The mixture was dried under vacuum below 40 °C to obtain the crude product. The crude product was then transferred to a 20 L reaction vessel, and 6 L of acetone and 500 mL of ethanol were added. The mixture was heated to reflux in a water bath and stirred for 1 hour. After cooling to 0 °C, the mixture was filtered and dried under vacuum overnight at 40 °C to obtain the pure compound 2, with a yield of 90%.
[0031] Weigh 1 kg of compound 2 and add it to a 50 L reaction vessel. Add 20 L of acetonitrile, under nitrogen protection, add 5 g of azobisisobutyronitrile (AIBN), and then add 150 mL of DBU. Heat to 65 °C, and slowly add 500 g of bromosuccinimide. React for 2 h. Filter, dissolve the solid in DCM, wash with saturated sodium bicarbonate solution, dry, and evaporate the filtrate under reduced pressure to obtain compound 3, yield 88%.
[0032] Weigh 1 kg of compound 3 and add it to a 20 L reaction vessel. Add 120 g of sodium hydroxide and 5 L of ethanol. Heat to 120 °C under nitrogen protection and react at this temperature for 2 h. Then add 5 L of acetonitrile / ethanol (volume ratio 1 / 1), recrystallize, filter, dry under vacuum, and dry at 40 °C overnight to obtain compound 4 with a yield of 91%.
[0033] 1 kg of compound 4 was added to a 50 L reaction vessel, along with 20 L of anhydrous acetonitrile, 1.2 g of 1,8-dihydroxyanthraquinone, and 0.5 g of hydroquinone as a polymerization inhibitor. Under nitrogen protection, the photochemical ring-opening reaction was performed at a wavelength of 275 nm at 0°C for 15 hours. The photochemical ring-closing reaction was performed at a wavelength of 335 nm at 0°C for 15 hours. The solvent was removed by vacuum distillation, and then 20 mL of a 2:1 (v / v) mixture of ethanol and acetonitrile was added. The mixture was heated to reflux for 30 minutes, cooled at 0°C, filtered, and recrystallized from isopropanol to obtain compound 5 in 76% yield.
[0034] Compound 5 was dissolved in ethyl acetate, 100 g of hydrochloric acid was added, and the reaction was carried out at 80 °C. After the reaction was completed, the solvent was removed under reduced pressure, extracted with DCM, washed with sodium bicarbonate solution until neutral, dried, and the solvent was recovered by distillation under reduced pressure. The mixture was then recrystallized with ethanol and filtered to obtain compound 6.
[0035] 100g of concentrated hydrochloric acid solution in 20L of tetrahydrofuran was added to the reaction vessel containing compound 6. The mixture was stirred at -10°C, then neutralized with sodium bicarbonate, extracted with DCM, washed with acetonitrile, and dried to obtain dydrogesterone compound 7 with a yield of 74% and a purity of 99.3%.
[0036] This invention utilizes specific acid, catalyst, polymerization inhibitor, and solvent conditions to prepare dydrogesterone with high purity and high yield, making it suitable for industrial production.
[0037] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.
Claims
1. A method for preparing dydrogesterone, characterized in that, It is prepared from progesterone through the following steps. Step one is ketalization, in which progesterone reacts in an organic solvent catalyzed by methanesulfonic acid. Step two is halogenation. Under anhydrous and oxygen-free conditions, N-bromosuccinimide, a free radical initiator, is added to an organic solvent to carry out the bromination reaction. Step 3 is an elimination reaction, which occurs under alkaline conditions; Step four is the photoreaction, under inert gas conditions, with the addition of a photocatalyst, polymerization inhibitor, and solvent, and the reaction is carried out at -20 to 30 degrees Celsius. Step five is deprotection, which is performed under acidic conditions; Step six is isomerization under acidic conditions to obtain the dydrogesterone product.
2. The method for preparing dydrogesterone according to claim 1, characterized in that, Step one includes one or more of the following features: A1) The reaction temperature is 20~50 degrees Celsius; A2) The organic solvent may be selected from one or more of petroleum ether, n-hexane, n-heptane, isooctane, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, ethyl acetate, isopropyl acetate, and butyl acetate.
3. The method for preparing dydrogesterone according to claim 1, characterized in that, Step two includes one or more of the following features: B1) The solvent is selected from one or more of carbon tetrachloride, chloroform, and acetonitrile; B2) The free radical initiator is selected from benzoyl peroxide or azobisisobutyronitrile; B3) The reaction temperature is selected from 30~80℃; B4) further includes post-treatment, which involves alkaline washing followed by distillation, column chromatography, or crystallization to separate the target product.
4. The method for preparing dydrogesterone according to claim 1, characterized in that, Step three includes one or more of the following features: C1) Use inorganic bases for alkalinity; C2) Use alcohol solvents.
5. The method for preparing dydrogesterone according to claim 1, characterized in that, Step four includes one or more of the following features: D1) The light reaction uses LED ultraviolet lamps with a wavelength range of 265-365nm. The first stage uses light of 265~300nm and the second stage uses light of 305~365nm. D2) The illumination time for the photoreaction is selected to be 10-50 hours; D3) The photocatalyst is selected from anthraquinone catalysts, preferably one or more of 1,8-dihydroxyanthraquinone, 1,4,5,8-tetrachloroanthraquinone, and 9,10-diacenic anthraquinone; D4) Use an anhydrous solvent, preferably anhydrous acetonitrile or anhydrous DMF; D5) The polymerization inhibitor selected is butylated hydroxytoluene; D6) The inert gas is selected from nitrogen and argon.
6. The method for preparing dydrogesterone according to claim 1, characterized in that, Step five includes the following features: E1) The acidic conditions are selected from one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and methanesulfonic acid, preferably methanesulfonic acid; E2) Solvents can be ethyl acetate, ethanol, etc.; E3) The temperature is 70~90 degrees Celsius.
7. The method for preparing dydrogesterone according to claim 1, characterized in that, Step six includes one or more of the following features: F1) The acidic condition is a Lewis acid, preferably zinc chloride; F2) The solvent is selected from one or more of DMF, DMSO, and acetonitrile; F3) Temperature is 20~50 degrees Celsius; F4 also includes post-treatment, which involves neutralization with an inorganic base.