Synthesis method of didrogesterone

Abstract

The invention discloses a synthetic method of didrogesterone, which takes progesterone as a raw material, comprises the steps of ketalation, bromination, elimination, photoreaction, deprotection, isomerization and the like, and emphatically researches the action of the combination of light with different wavelengths on the open-loop process and the closed-loop process of the photoreaction in the photoreaction process and the design of a kettle type photoreactor. And carrying out double-bond isomerization reaction under the condition of Lewis acid catalysis. The process is high in total yield and suitable for production amplification, the photoreactor is simple in structure and easy to process and manufacture, a light source is cheap and easy to obtain, and the reaction yield is stable.

Description

[0001] This application claims the priority of the prior application filed by the applicant with the State Intellectual Property Office of China on June 29, 2023, with patent application number 202310785367.8 and titled “A Synthesis Method and Production Process of Dydrogesterone”. The entire text of the prior application is incorporated into this disclosure by reference. Technical Field

[0002] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing dydrogesterone. Background Art

[0003] Dydrogesterone, chemically named 9β,10α-pregnane-4,6-diene-3,20-dione, is a commonly used gynecological drug used to treat diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, and infertility caused by corpus luteum deficiency. Compared with other progesterone drugs, its advantage is that dydrogesterone increases double bonds at C6 and C7 and reverses the configuration of carbon atoms at C9 and C10, making its molecular configuration highly selective for progesterone receptors, and has no estrogen, androgen, anti-androgen, glucocorticoid, and anti-mineralocorticoid activity, which greatly reduces the incidence of adverse drug reactions, and is therefore widely used.

[0004] The drug was first developed by the Dutch company Solvay Pharmaceuticals BV in 1961 and marketed worldwide. It has been registered in more than 60 countries and sold in more than 150 countries and regions. In 2020, my country's sales were about 900 million yuan, and its sales worldwide are still growing. Solvay Pharmaceuticals was acquired by Abbott in 2009. As of 2022, Abbott is still the only company that sells dydrogesterone tablets on the market, and its technical route has not been made public. In order to boost my country's self-sufficiency rate of steroid drugs, it is urgent to solve the technical difficulties of independently synthesizing dydrogesterone APIs, and at the same time provide the necessary material conditions for the development of other compound preparations.

[0005] There are many patents for the synthesis of dydrogesterone, which can be roughly divided into two parts according to the availability of raw materials: one is the synthesis route using cheap and readily available progesterone and its precursors as raw materials; the other is the synthesis route using relatively difficult to obtain compounds as raw materials, such as: using luminosterol, ergosterol, trans-progesterone, etc., as well as synthetic progesterone as starting materials, and the synthesis route is longer. The most widely studied route for the synthesis of dydrogesterone using progesterone as raw material can be roughly summarized as follows:

[0006]

[0007] The core technical difficulty of this route lies in the photoreaction process of converting 5,7-dehydroprogesterone diethylene glycol to 9β,10α-5,7-dehydroprogesterone diethylene glycol. Since this process goes through two processes, ring opening and ring closing, the intermediate after ring opening is easily rearranged to become an intermediate with a double bond trans structure, resulting in the inability to undergo the light closure process shown below or the polymerization reaction to obtain polymer impurities. In addition, the light wavelengths that control the ring opening and closing processes are different, and most of the light waves that can achieve the ring closing process will lead to double bond trans isomerization reactions of the ring opening intermediates. Therefore, the wavelength selection of the closed-loop illumination becomes particularly important.

[0008]

[0009] Another process that affects the reaction yield is the step of isomerizing the deprotected intermediate 9β,10α-7-dehydroprogesterone to dydrogesterone. All currently known technical routes involving this reaction process use proton acid or base catalysis for isomerization, but there are relatively serious side reactions. Through research, it was found that if proton acid catalysis is used, taking hydrogen chloride as an example, a large amount of hydrogen chloride and 7-position double bond addition products and their conversion products will be produced, accompanied by a certain amount of double bond polymerization byproducts, etc.; if base catalysis is used, a large amount of impurities such as polymers will also be produced, and only a small amount of products will be obtained, which is difficult to achieve industrial production.

[0010]

[0011] Based on the research on the above issues, it is urgent to find a more effective synthesis method suitable for the industrial production of dydrogesterone. Summary of the invention

[0012] In order to solve the problems existing in the prior art, the present invention provides the following solution: using progesterone as a starting material, dydrogesterone is obtained through ketalization, bromination, elimination, photoisomerization reaction, hydrolysis, and double bond isomerization.

[0013] The present invention provides a method for preparing a dydrogesterone precursor compound e, comprising the following steps 4: adding a compound d, a solvent D, a photocatalyst, and an inhibitor into a photoreactor, adjusting the temperature of the reaction liquid to -20°C to 30°C, and performing a photochemical reaction to obtain a compound e;

[0014]

[0015] in, does not exist or is a single bond; X is selected from halogen, such as Br or Cl;

[0016] when When not present, R1 and R2 are the same or different and are independently selected from C 1-6 Alkyl; for example, methyl;

[0017] when When it is a single bond, R1 and R2 are the same or different and are independently selected from C 1-6 Alkylene; for example, methylene;

[0018] The photochemical reaction is selected from one of the following methods A, B or C:

[0019] Method A: adjust the temperature of the reaction solution to -20°C to 30°C, turn on light source A for 2h-4h, turn off light source A, turn on light source B for 6h-8h, turn off light source B, and repeat 3 times;

[0020] Method B: adjust the temperature of the reaction solution to -20°C to 30°C, turn on light source C for 4h-6h, then turn on light source D for 16h-20h, turn off light source C, and turn off light source D after 4h-6h;

[0021] Method C: adjust the temperature of the reaction solution to -20°C to 30°C, turn on light source E for 20h-24h, turn off light source E, turn on light source F for 4h-6h, and turn off light source F;

[0022] The solvent D is selected from hydrocarbon solvents, ether solvents, alcohol solvents, and ester solvents; preferably, the solvent D is selected from one or more of n-hexane, n-heptane, isooctane, tetrahydrofuran, methyltetrahydrofuran, dioxane, methanol, ethanol, isopropanol, and ethyl acetate; more preferably, the solvent D is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, ethyl acetate, isooctane, ethanol, and methanol.

[0023] The photocatalyst is selected from 5,10-di(2-naphthyl)-5,10-dihydrophenazine, 1,2,4,5-tetracyanobenzene, 10-phenyl-10H-phenothiazine, anthraquinone, 1,8-dihydroxyanthraquinone, 1,4,5,8-tetrachloroanthraquinone, 9,10-dinitrile anthracene, 2-isopropylthioxanthone, 2-chloro-9-thioxanthone, 2-iodo-9-thioxanthone, 1,4-dinitrile naphthalene, 1, One or more of 4-dichloronaphthalene, quinoxaline, 2,3-dihydroxyquinoxaline, and 2,3-dichloroquinoxaline; preferably, the photocatalyst is selected from 1,4,5,8-tetrachloroanthraquinone, 1,4-dinitrile naphthalene, 2,3-dihydroxyquinoxaline, 1,4-dichloronaphthalene, 9,10-dinitrile anthracene, 2-isopropylthioxanthone, 2-iodo-9-thioxanthone, quinoxaline, and 1,8-dihydroxyanthraquinone.

[0024] The polymerization inhibitor is selected from one or more of 2,6-dimethyl-4-tert-butylphenol, hydroquinone, 1,4-naphthalene diol, and 5,8-dihydroxy-1,4-naphthoquinone;

[0025] The wavelength of the light source A is selected from 225-345 nm, for example 245-325 nm, such as 245 nm, 254 nm, 265 nm, 275 nm, 295 nm, 305 nm, 315 nm, 325 nm, or a combination of several wavelengths;

[0026] The wavelength of the light source B is selected from 250-360 nm, for example, 275-340 nm, such as 275 nm, 295 nm, 305 nm, 315 nm, 325 nm, 335 nm, 340 nm, or a combination of several wavelengths;

[0027] The wavelength of the light source C is selected from 225-315 nm, for example, 245-295 nm, such as one or a combination of 245 nm, 254 nm, 265 nm, 275 nm, 295 nm;

[0028] The wavelength of the light source D is selected from 315-360nm, for example, 295-340nm, such as 295nm, 305nm, 315nm, 325nm, 335nm, 340nm, or a combination of several wavelengths;

[0029] The wavelength of the light source E is selected from 234-335 nm, for example, 254-315 nm, such as 254 nm, 265 nm, 275 nm, 285 nm, 295 nm, 305 nm, 315 nm, or a combination of several wavelengths;

[0030] The wavelength of the light source F is selected from 285-360 nm, for example, 305-340 nm, such as 305 nm, 315 nm, 325 nm, 335 nm, 340 nm, or a combination of several wavelengths.

[0031] According to some embodiments, step 4 may further include purification steps 4-2 to 4-4:

[0032] 4-2: After the reaction is completed, the reaction solution is evaporated to remove the solvent, and the residue is washed with solvent D1 at -10°C to 50°C for 0.5h-1h, and filtered to obtain D1 filtrate and D1 filter residue, which can be recovered as raw material compound d;

[0033] 4-3: After the solvent is evaporated from the filtrate D1 in step 4-2, the mixture is washed with solvent D2 at -10°C to 50°C for 0.5h-1h, and filtered to obtain mother liquor D2 and crude compound e;

[0034] 4-4: Recrystallizing the crude compound e with solvent D3 to obtain D3 mother liquor and purified compound e;

[0035] According to some embodiments, in step 4, the purification step may further include steps 4-5:

[0036] 4-5: After mixing the mother liquor D2 with the mother liquor D3, the solvent is evaporated to recover the ring-opening intermediate, which is then combined with the recovered raw material compound d. Repeating the process with the raw material can achieve an effective conversion rate of 75%-85% for converting compound d into compound e.

[0037] According to some embodiments, in step 4-2, the solvent D1 is selected from one or more of acetonitrile, acetone, methanol, ethanol, isopropanol, n-hexane, and ethyl acetate.

[0038] According to some embodiments, in step 4-3, the solvent D2 is selected from one or more of acetonitrile, acetone, methanol, ethanol, isopropanol, n-hexane, and dichloromethane.

[0039] According to some embodiments, in step 4-4, the solvent D3 is selected from one or more of acetonitrile, acetone, butanone, methanol, ethanol, isopropanol, n-hexane, n-heptane, dichloromethane, and ethyl acetate.

[0040] According to some embodiments, the preparation method of compound d comprises the following steps:

[0041]

[0042] in, , X, R1, and R2 have the definitions described in the present invention;

[0043] Step 1: Compound a (progesterone) reacts with compound a1 to obtain compound b; compound a1 is selected from R1-OH, R2-OH and / or

[0044] Step 2: Compound b reacts with a halogenating agent to obtain compound c;

[0045] Step 3: Compound c undergoes elimination reaction to obtain compound d;

[0046] According to some embodiments, step 1 can be carried out in the presence of solvent A, wherein solvent A is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, toluene, cyclohexane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether. Preferably, solvent A is selected from one or more of N,N-dimethylformamide, toluene, cyclohexane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether.

[0047] According to some embodiments, step 1 can be carried out in the presence of catalyst A, wherein catalyst A is selected from one or more of sulfuric acid, aminosulfonic acid, concentrated hydrochloric acid, oxalyl chloride, acetyl chloride, and trifluoroacetic acid. Preferably, catalyst A is selected from one or more of aminosulfonic acid, oxalyl chloride, and acetyl chloride.

[0048] According to some embodiments, step 1 can be carried out in the presence of a dehydrating agent A, wherein the dehydrating agent A is selected from one or more of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, 2,2-dimethoxypropane, and dimethoxymethane. Preferably, the dehydrating agent A is selected from one or more of trimethyl orthoformate, trimethyl orthoacetate, and triethyl orthoformate.

[0049] According to some embodiments, step 1 may also include a purification step: after the reaction is completed, solvent A is evaporated, solvent A1 and sodium carbonate are added, and stirring is continued, and then an organic phase is extracted to obtain an organic phase. After removing the organic phase solvent, solvent A2 is added to disperse and filter to obtain a purified compound b.

[0050] According to some embodiments, the solvent A1 is 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.

[0051] According to some embodiments, the solvent A2 is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, ethylene glycol monomethyl ether, cyclohexane, n-heptane, and isooctane.

[0052] According to some embodiments, step 2 can be carried out in the presence of solvent B, wherein solvent B is selected from one or more of cyclohexane, n-heptane, isooctane, petroleum ether, tetrahydrofuran, dioxane, chloroform, and carbon tetrachloride. Preferably, solvent B is selected from one or more of cyclohexane, dioxane, n-heptane, and carbon tetrachloride.

[0053] According to some embodiments, step 2 can be carried out in the presence of an acid binding agent, wherein the acid binding agent is selected from one or more of pyridine, 4-methylpyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, potassium carbonate, and sodium carbonate. Preferably, the acid binding agent is selected from one or more of 2,6-lutidine, 2,4,6-trimethylpyridine, and pyridine.

[0054] According to some embodiments, in step 2, the halogenating agent may be selected from one or more of N-bromosuccinimide, dibromohydantoin, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, N-chlorosuccinimide, and dichlorohydantoin. Preferably, the halogenating agent may be selected from dibromohydantoin, N-bromosuccinimide, and 2,4,4,6-tetrabromo-2,5-cyclohexadienone.

[0055] According to some embodiments, step 3 can be carried out in the presence of solvent C, wherein the solvent C is selected from one or more of n-heptane, isooctane, toluene, xylene, pyridine, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether. Preferably, solvent C is selected from one or more of toluene, pyridine, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether.

[0056] According to some embodiments, step 3 can be carried out in the presence of an organic base A, wherein the organic base A is selected from one or more of 2,6-lutidine, 2,4,6-trimethylpyridine, triethylamine, and diisopropylethylamine. Preferably, the organic base A is selected from 2,6-lutidine, 2,4,6-trimethylpyridine, and triethylamine.

[0057] According to some embodiments, step 3 may further include a purification step: after the reaction is completed, solvent C is evaporated, solvent C1 is added to disperse, and the crude compound d is obtained by filtering, and solvent C1 is added again, heated and stirred, and then cooled to precipitate, and filtered to obtain compound d.

[0058] According to some embodiments, the solvent C1 is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, petroleum ether, cyclohexane, n-hexane, n-heptane, and isooctane. Preferably, the solvent C1 is selected from one or more of acetonitrile, petroleum ether, isopropanol, and n-hexane.

[0059] The present invention provides a method for preparing compound G (dydrogesterone), comprising the following steps:

[0060]

[0061] in, , R1, R2 have the definitions described in the present invention; step 4 is according to the preparation method described in the present invention;

[0062] Step 4: Add compound d, solvent D, photocatalyst, and polymerization inhibitor into a photoreactor, adjust the temperature of the reaction solution to -20°C to 30°C, and perform a photochemical reaction to obtain compound e;

[0063] Step 5: Compound e is subjected to a deprotection reaction to obtain compound f (intermediate 5, i.e., 9β,10α-7-dehydroprogesterone);

[0064] Step 6: Compound f undergoes double bond isomerization reaction to obtain compound g (dydrogesterone).

[0065] According to some embodiments, step 5 can be performed in the presence of solvent E, wherein the solvent E is selected from one or more of acetone, methanol, ethanol, isopropanol, and water.

[0066] According to some embodiments, step 5 can be carried out in the presence of catalyst B, wherein catalyst B is selected from one or more of sulfuric acid, sodium bisulfate, p-toluenesulfonic acid, aminosulfonic acid, hydrochloric acid, and phosphoric acid.

[0067] According to some embodiments, step 6 can be carried out in the presence of a solvent F, wherein the solvent F is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, n-heptane, toluene, acetonitrile, acetone, methanol, ethanol, isopropanol, and water.

[0068] According to some embodiments, step 6 can be carried out in the presence of a catalyst C, wherein the catalyst C is selected from one or more of zinc chloride, manganese chloride, ferrous chloride, cupric acetate, potassium iodide, sodium iodide, lithium bromide, cobalt chloride, zinc acetate, titanium trichloride, zinc iodide, manganese (III) acetylacetonate, manganese (III) acetyphenacetonate, aluminum triacetylacetonate, vanadium diacetylacetonate, zirconium acetylacetonate, trimethylsilyl iodide, and iodine.

[0069] According to some embodiments, step 6 may further include a purification step: after the reaction is completed, neutralize with sodium bicarbonate solution, extract to obtain an organic phase, evaporate the solvent of the organic phase, dissolve the residue with solvent F1, stir and wash at -10°C-80°C for 1h-4h, and filter to obtain the compound g.

[0070] According to some embodiments, the solvent F1 is selected from one or more of acetonitrile, acetone, methanol, ethanol, isopropanol, n-hexane, petroleum ether, and dichloromethane.

[0071] According to some embodiments, the preparation method further comprises the step of refining compound g:

[0072] Step 7: Dissolve the compound g obtained in step 6 in solvent G, heat to reflux temperature to dissolve, cool to -15°C to 25°C, precipitate a white solid, filter to obtain purified compound g.

[0073] According to some embodiments, the solvent G is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, ethylene glycol monomethyl ether, cyclohexane, n-heptane, isooctane, and petroleum ether.

[0074] According to an exemplary embodiment of the present invention, the preparation method comprises the following steps:

[0075]

[0076] Step 1: Synthesis of intermediate 1 (5-dehydroprogesterone diethylene ketal)

[0077] Add progesterone and ethylene glycol to solvent A and heat to dissolve, add catalyst A, raise the temperature to the reaction temperature, start to slowly drip dehydrating agent A, drip for about 16h-24h, continue to react for 2h-4h after dripping, and the reaction is finished. Evaporate solvent A, add solvent A1 and sodium carbonate, continue stirring for 0.5h, wash the organic layer with brine 3 times, separate the organic layer, evaporate the solvent, add solvent A2 to disperse, filter, rinse, and dry under reduced pressure to constant weight to obtain 5-dehydroprogesterone diethylene ketal.

[0078] Step 2: Synthesis of intermediate 2 (6-bromo-5-dehydroprogesterone diethyl ketal)

[0079] Dissolve 5-dehydroprogesterone diethylene ketal in solvent B, heat to dissolve, add acid binding agent, raise the temperature to 50°C-75°C, then add bromination reagent in batches, react for 0.5h-2h after addition, filter while hot, and then evaporate the solvent to obtain a mixture of 6-bromo-5-dehydroprogesterone diethylene ketal, which is directly used in the next reaction.

[0080] Step 3: Synthesis of intermediate 3 (5,7-dehydroprogesterone diethyl ketal)

[0081] The mixture obtained in the previous step was dissolved in solvent C, and then organic base A was added, and the temperature was raised to 70°C-115°C for elimination. The reaction was carried out for about 2h-4h. The raw materials were monitored to be basically reacted. The temperature was lowered, and solvent C was evaporated. Solvent C1 was added to disperse and filtered to obtain a crude product of 5,7-dehydroprogesterone diethylene ketal. Solvent C1 was added again, and the temperature was lowered to precipitate after heating and stirring. The product was filtered and dried to constant weight to obtain 5,7-dehydroprogesterone diethylene ketal.

[0082] Step 4: Synthesis of intermediate 4 (9β,10α-5,7-dehydroprogesterone diethyl ketal)

[0083] 4-1: Dissolve 5,7-dehydroprogesterone diethylene acetal in solvent D, add a photocatalyst and an inhibitor, and then transfer the solution into a photoreactor, adjust it to a suitable temperature (-20°C to 30°C), and carry out a photochemical reaction by one of methods A, B, and C.

[0084] Method A: Adjust the reaction solution to an appropriate temperature (-20°C to 30°C), turn on light source A for 2h-4h, turn off light source A, turn on light source B for 6h-8h, turn off light source B, and repeat 3 times.

[0085] Method B: adjust the reaction solution to an appropriate temperature (-20°C to 30°C), turn on light source C to irradiate for 4h-6h, then turn on light source D to irradiate for 16h-20h, turn off light source C, and turn off light source D after 4h-6h.

[0086] Method C: adjust the reaction solution to an appropriate temperature (-20°C to 30°C), turn on light source E to irradiate for 20h-24h, turn off light source E, turn on light source F to irradiate for 4h-6h, and turn off light source F.

[0087] 4-2: After the reaction is completed, the solvent is evaporated from the reaction solution, and the residue is washed with solvent D1 at -10°C to 50°C for 0.5h-1h, filtered, and the raw material (5,7-dehydroprogesterone diethylene ketal) is recovered.

[0088] 4-3: After the solvent is evaporated from the filtrate of D1, the mixture is washed with solvent D2 at -10°C to 50°C with stirring for 0.5h-1h, and filtered to obtain the crude product of 9β,10α-5,7-dehydroprogesterone diethyl ketal.

[0089] 4-4: The crude product was recrystallized with solvent D3 to obtain pure 9β,10α-5,7-dehydroprogesterone diethyl ketal.

[0090] 4-5: Mix the D2 mother liquor with the D3 mother liquor, evaporate the solvent and recover the ring-opening intermediate, then combine it with the recovered raw material, and replace it with the raw material and repeat the process from 4-1.

[0091] Step 5: Synthesis of intermediate 5 (9β,10α-7-dehydroprogesterone)

[0092] Dissolve 9β,10α-5,7-dehydroprogesterone diethyl ketal in solvent E, add catalyst B, raise the temperature to 30°C-100°C, react for 1h-4h, monitor the complete reaction of the raw material and the intermediate, cool down, neutralize with sodium bicarbonate solution, precipitate solid, filter, rinse with water, and dry under reduced pressure at 30°C-50°C to constant weight to obtain 9β,10α-7-dehydroprogesterone.

[0093] Step 6: Synthesis of Dydrogesterone

[0094] Dissolve 9β,10α-7-dehydroprogesterone in solvent F, add catalyst C, and react at -15°C-110°C for 2h-16h. When the remaining raw material is <0.5% as monitored by HPLC, stop the reaction, neutralize with sodium bicarbonate solution, add DCM for extraction, evaporate the solvent, and then wash with solvent F1 solution at -10°C-80°C for 1h-4h, filter, rinse, and dry to obtain crude dydrogesterone.

[0095] Step 7: Refining of Dydrogesterone

[0096] The crude dydrogesterone was dissolved in solvent G, heated to reflux temperature to dissolve, and slowly cooled to -15°C to 25°C to precipitate a white solid. The mixture was stirred for 1 h to 2 h, filtered, rinsed, and dried under reduced pressure at 30°C to 50°C to constant weight to obtain pure dydrogesterone.

[0097] According to some embodiments, the photochemical reaction process of the present invention can be completed in a kettle-type photoreactor, and the kettle-type photoreactor is provided with an even number of 6 or more light sources.

[0098] In some embodiments, the kettle-type photoreactor can be obtained by modifying a reactor with interlayer glass or other materials, punching a circular hole inward from the kettle cover, inserting a quartz glass liner, inserting an LED light source lamp group with a heat sink or other customized light source, the number of holes is an even number of 6 or more, and light sources of different wavelengths are arranged alternately. The structural schematic diagram is shown in the attached figure. Figure 7 .

[0099] According to some embodiments, the light source used in the photochemical reaction process of the present invention must meet the following optical properties: the light source involved in the present invention is an LED light source or other types of customized light sources, which must meet the half-peak width of 8nm≤λ≤12nm. The data is detected by USB2000+ fiber optic spectrometer and there are no other wavelength peaks.

[0100] Impurity 7-Dehydroprogesterone 1 H-NMR is the main impurity of dydrogesterone (see pharmacopoeia), and its NMR spectrum is attached Figure 6 When the raw material (5,7-dehydroprogesterone diethylene ketal) that has not undergone photoreaction remains in the irradiated product, this impurity will be produced in the subsequent reaction process. The various steps of the embodiment of the present invention are effectively purified, and this substance is not detected in the final product dydrogesterone.

[0101] The method conditions described in the present invention can be arbitrarily combined without violating the common sense within the technical background, and are not limited to the scope covered by the embodiments; the combination of the photoreactor design method and the light source wavelength can also be arbitrarily combined.

[0102] Beneficial Effects

[0103] The positive effect of the present invention is that it provides an industrially scalable method for synthesizing dydrogesterone from progesterone as a raw material, covers the optimization of the photoreaction process and the design ideas of an industrially scalable photoreactor, and solves the key problem of low yield of photoreaction conversion of 5,7-dehydroprogesterone diethylene ketal into 9β,10α-5,7-dehydroprogesterone diethylene ketal and isomerization of 9β,10α-7-dehydroprogesterone to dydrogesterone, thereby achieving the purpose of industrially scalable high conversion rate synthesis of dydrogesterone, and has significant social significance and commercial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Attached Figure 1 5-Dehydroprogesterone diethyl ketal 1 H-NMR

[0105] Attached Figure 25,7-Dehydroprogesterone diethyl ketal 1 H-NMR

[0106] Attached Figure 3 9β,10α-5,7-dehydroprogesterone diethyl ketal 1 H-NMR

[0107] Attached Figure 4 9β,10α-7-dehydroprogesterone 1 H-NMR

[0108] Attached Figure 5 Dydrogesterone 1 H-NMR

[0109] Attached Figure 6 Impurity 7-Dehydroprogesterone 1 H-NMR

[0110] Attached Figure 7 Schematic diagram of the design of a kettle photoreactor DETAILED DESCRIPTION

[0111] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

[0112] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0113] Example 1 Synthesis of 5-dehydroprogesterone diethylene ketal

[0114] Add 94.4g of progesterone and 148.8g of ethylene glycol to a mixture of 100mL of N,N-dimethylformamide and 300mL of ethylene glycol dimethyl ether, heat to dissolve, add 0.3g of aminosulfonic acid, raise the temperature to 55℃-60℃, and slowly add 79.6g of trimethyl orthoformate, and add for about 16h. After the addition is complete, continue to react for 2h, and the reaction is completed. Most of the solvent is evaporated under reduced pressure, and 300mL of n-hexane and 300mL of dichloromethane and 5g of sodium carbonate are added. Stirring is continued for 0.5h, and the organic layer is washed with saturated brine for 3 times. The organic layer is separated, the solvent is evaporated, and 300mL of methanol is added to disperse, filter, rinse with methanol, and dry under reduced pressure to constant weight to obtain 5-dehydroprogesterone diethylene ketal with a yield of 91.5% and a liquid phase purity of >99%. 5-dehydroprogesterone diethylene ketal 1 H-NMR as attached Figure 1 shown.

[0115] Example 2 Synthesis of 5-dehydroprogesterone diethylene ketal

[0116] Add 1200 mL of methyl tert-butyl ether to 188.8 g of progesterone and 260.4 g of ethylene glycol, heat to dissolve, add 0.4 g of oxalyl chloride, heat to 50°C-55°C, slowly add 231.2 g of triethyl orthoformate, add for about 20 hours, continue to react for 4 hours after the dripping is complete, and the reaction is completed. Evaporate the solvent, add 600 mL of petroleum ether and 600 mL of dichloromethane, and 10 g of sodium carbonate, continue stirring for 0.5 hours, wash the organic layer with brine 3 times, separate the organic layer, evaporate the solvent, add 500 mL of ethanol to disperse, filter, rinse with ethanol, and dry under reduced pressure to constant weight to obtain 5-dehydroprogesterone diethylene ketal with a yield of 93.3% and a liquid phase purity of >99%.

[0117] Example 3 Synthesis of 5-dehydroprogesterone diethylene ketal

[0118] Add 157.3 g of progesterone and 188.1 g of ethylene glycol to a mixture of 2000 mL of cyclohexane and 500 mL of ethylene glycol diethyl ether, heat to dissolve, add 1.2 g of acetyl chloride, raise the temperature to 60°C-65°C, slowly add 166.2 g of trimethyl orthoacetate, add for about 24 hours, continue to react for 3 hours after the dripping is complete, and the reaction is completed. Evaporate the solvent, add 2000 mL of ethyl acetate and 8 g of sodium carbonate, continue stirring for 0.5 hours, wash the organic layer with brine 3 times, separate the organic layer, evaporate the solvent, add 2000 mL of acetone to disperse, filter, rinse with acetone, and dry under reduced pressure to constant weight to obtain 5-dehydroprogesterone diethylene acetal with a yield of 93.7% and a liquid phase purity of >99%.

[0119] Example 4 Synthesis of 6-bromo-5-dehydroprogesterone diethyl ketal

[0120] Dissolve 120.8 g of 5-dehydroprogesterone diethyl ketal in 2400 mL of cyclohexane, heat until dissolved, add 38.6 g of 2,6-lutidine, raise the temperature to 65°C-70°C, then add 150.1 g of dibromohydantoin in 10 portions with an interval of 5 minutes. React for 1.2 hours after addition, filter while hot, and then evaporate the solvent to obtain a mixture of 6-bromo-5-dehydroprogesterone diethyl ketal, which is directly used in the next reaction.

[0121] Example 5 Synthesis of 6-bromo-5-dehydroprogesterone diethyl ketal

[0122] Dissolve 201.3 g of 5-dehydroprogesterone diethylene ketal in 2000 mL of cyclohexane and 400 mL of dioxane, heat until dissolved, add 30.3 g of 2,4,6-trimethylpyridine and 55.2 g of potassium carbonate, raise the temperature to 60°C-70°C, and then add 97.5 g of N-bromosuccinimide in 10 portions with an interval of 5 minutes. After the addition is completed, react for 0.75 hours, filter while hot, and then evaporate the solvent to obtain a mixture of 6-bromo-5-dehydroprogesterone diethylene ketal, which is directly used in the next reaction.

[0123] Example 6 Synthesis of 6-bromo-5-dehydroprogesterone diethyl ketal

[0124] Dissolve 241.6 g of 5-dehydroprogesterone diethylene ketal in 3600 mL of n-heptane and 480 mL of carbon tetrachloride, heat until dissolved, add 51.5 g of pyridine and 55.3 g of sodium carbonate, raise the temperature to 70°C-75°C, and then add 249.4 g of 2,4,4,6-tetrabromo-2,5-cyclohexadienone in 8 portions with an interval of 5 minutes. After the addition is completed, react for 1.5 hours, filter while hot, and then evaporate the solvent to obtain a mixture of 6-bromo-5-dehydroprogesterone diethylene ketal, which is directly used in the next reaction.

[0125] Example 7 Synthesis of 5,7-dehydroprogesterone diethylene ketal

[0126] The mixture of 6-bromo-5-dehydroprogesterone diethylene ketal obtained in Example 4 was dissolved in 1200 mL of toluene, and 43.6 g of 2,4,6-trimethylpyridine was added, and the temperature was raised to 95°C-100°C for elimination. The reaction was carried out for about 3 hours. The raw materials were monitored to be basically reacted completely, and the temperature was lowered. The solvent was evaporated, and 600 mL of acetone was added to disperse and filtered to obtain a crude 5,7-dehydroprogesterone diethylene ketal. 500 mL of acetone was added, and the mixture was heated to 30°C and stirred for 10 min, then cooled to -10°C for precipitation, filtered, and dried to constant weight to obtain 5,7-dehydroprogesterone diethylene ketal. The two-step yield was 47.3%, and the liquid phase purity was >99%.

[0127] Example 8 Synthesis of 5,7-dehydroprogesterone diethylene ketal

[0128] The mixture of 6-bromo-5-dehydroprogesterone diethylene ketal obtained in Example 5 was dissolved in a mixture of 200 mL of pyridine and 600 mL of ethylene glycol dimethyl ether, and then 10.1 g of triethylamine was added, and the temperature was raised to reflux temperature for elimination. The reaction was carried out for about 4 hours, and the raw materials were monitored to be basically reacted. The temperature was lowered, the solvent was evaporated, and 800 mL of acetonitrile was added for dispersion. The crude product of 5,7-dehydroprogesterone diethylene ketal was obtained. 600 mL of acetonitrile was added, and the mixture was heated to 40°C and stirred for 10 minutes, then cooled to -10°C for precipitation, filtered, and dried to constant weight to obtain 5,7-dehydroprogesterone diethylene ketal. The two-step yield was 48.4%, and the liquid phase purity was >99%. 5,7-dehydroprogesterone diethylene ketal 1 H-NMR as attached Figure 2 shown.

[0129] Example 9 Synthesis of 5,7-dehydroprogesterone diethylene ketal

[0130] The mixture of 6-bromo-5-dehydroprogesterone diethylene ketal obtained in Example 6 was dissolved in 1500 mL of ethylene glycol diethyl ether, and 80.0 g of 2,4,6-trimethylpyridine was added, and the temperature was raised to 110° C.-115° C. for elimination, and the reaction was carried out for about 2 hours. The raw materials were monitored to be basically reacted completely, and the temperature was lowered. The solvent was evaporated under reduced pressure, and a mixture of 500 mL of isopropanol and 1000 mL of n-hexane was added to disperse and filter to obtain a crude 5,7-dehydroprogesterone diethylene ketal. 400 mL of isopropanol and 800 mL of n-hexane were added to the solvent, and the mixture was heated and stirred, and then cooled to precipitate, filtered, and dried to constant weight to obtain 5,7-dehydroprogesterone diethylene ketal. The two-step yield was 46.7%, and the liquid phase purity was >99%.

[0131] Example 10 Synthesis of 5,7-dehydroprogesterone diethylene ketal

[0132] The mixture of 6-bromo-5-dehydroprogesterone diethylene ketal obtained in Example 4 was dissolved in a mixture of 1200 mL of n-heptane and 360 mL of ethylene glycol diethyl ether, and then 35.4 g of 2,6-lutidine was added, and the temperature was raised to 100° C.-105° C. for elimination, and the reaction was carried out for about 3 hours. The raw materials were monitored to be basically reacted completely, and the temperature was lowered, and the solvent was evaporated. Then, a mixture of 800 mL of petroleum ether and 100 mL of isopropanol was added to disperse and filter to obtain a crude 5,7-dehydroprogesterone diethylene ketal. Then, 600 mL of petroleum ether and 60 mL of isopropanol were added, and the mixture was heated and stirred, and then the temperature was lowered to precipitate, filtered, and dried to constant weight to obtain 5,7-dehydroprogesterone diethylene ketal, with a two-step yield of 47.5% and a liquid phase purity of >99%.

[0133] Example 11 Synthesis of 9β,10α-5,7-dehydroprogesterone diethylene ketal

[0134] The lighting method adopts method A, and other conditions refer to the following table:

[0135]

[0136] At room temperature, 20 g of intermediate 3 (5,7-dehydroprogesterone diethylene ketal), 1000 mL of tetrahydrofuran, 2 g (20 ppm) of 1,4,5,8-tetrachloroanthraquinone, and 5 g (50 ppm) of 2,6-dimethyl-4-tert-butylphenol were added to the photoreactor in sequence; light source A (245 nm and 275 nm) was turned on, and irradiation was performed at 5°C for 3 h; the light source was turned off, and light source B (295 nm and 315 nm) was turned on, and irradiation was performed at 10°C for 8 h, and light source B was turned off; the process was repeated 3 times.

[0137] The solvent was evaporated from the reaction solution, 100 mL of methanol was added to the residue, the mixture was stirred at 15° C., and filtered to obtain a filtrate and a filter residue, wherein the filter residue was recovered as a raw material intermediate 3.

[0138] The solvent was evaporated from the filtrate, and 100 mL of acetone was added. The mixture was stirred at 10°C and filtered to obtain a crude intermediate 4 and an acetone mother liquor.

[0139] The crude intermediate 4 was recrystallized at 0° C. using 80 mL of acetonitrile to obtain pure 9β,10α-5,7-dehydroprogesterone diethyl ketal and acetonitrile mother liquor.

[0140] The acetone mother liquor and the acetonitrile mother liquor were mixed and the solvent was evaporated, and the remaining solid was combined with the recovered raw material intermediate 3, and the above operation was repeated.

[0141] The total yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 80.5%, and the liquid phase purity was >99%. 1 H-NMR as attached Figure 3 shown.

[0142] Example 12 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0143] The operation is as in Example 11, the illumination method is method A, and other conditions are as in the following table:

[0144]

[0145] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal is 82.2% and the liquid phase purity is more than 99%.

[0146] Example 13 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0147] The operation is as in Example 11, the illumination method is method A, and other conditions are as in the following table:

[0148]

[0149] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 81.6% and the liquid phase purity was >99%.

[0150] Example 14 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0151] The operation is as in Example 11, the illumination method is method A, and other conditions are as in the following table:

[0152]

[0153] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 75.5%, and the liquid phase purity was more than 99%.

[0154] Example 15 Synthesis of 9β,10α-5,7-dehydroprogesterone diethylene ketal

[0155] The operation is as in Example 11, the illumination method is method A, and other conditions are as in the following table:

[0156]

[0157] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 74.7% and the liquid phase purity was more than 99%.

[0158] Example 16 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0159] The operation is as in Example 11, the illumination method is method B, and other conditions are as in the following table:

[0160]

[0161]

[0162] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 81.1% and the liquid phase purity was more than 99%.

[0163] Example 17 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0164] The operation is as in Example 11, the illumination method is method B, and other conditions are as in the following table:

[0165]

[0166] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal is 84.4%, and the liquid phase purity is more than 99%.

[0167] Example 18 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0168] The operation is as in Example 11, the illumination method is method B, and other conditions are as in the following table:

[0169]

[0170] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 78.2% and the liquid phase purity was more than 99%.

[0171] Example 19 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0172] The operation is as in Example 11, the illumination method is method B, and other conditions are as in the following table:

[0173]

[0174]

[0175] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 75.3% and the liquid phase purity was more than 99%.

[0176] Example 20 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0177] The operation is as in Example 11, the illumination method is method B, and other conditions are as in the following table:

[0178]

[0179] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 81.2% and the liquid phase purity was more than 99%.

[0180] Example 21 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0181] The operation is as in Example 11, the illumination method is method C, and other conditions are as in the following table:

[0182]

[0183] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 76.1% and the liquid phase purity was more than 99%.

[0184] Example 22 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0185] The operation is as in Example 11, the illumination method is method C, and other conditions are as in the following table:

[0186]

[0187]

[0188] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal is 81.7% and the liquid phase purity is more than 99%.

[0189] Example 23 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0190] The operation is as in Example 11, the illumination method is method C, and other conditions are as in the following table:

[0191]

[0192] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 77.4% and the liquid phase purity was more than 99%.

[0193] Example 24 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0194] The operation is as in Example 11, the illumination method is method C, and other conditions are as in the following table:

[0195]

[0196] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal was 82.1% and the liquid phase purity was more than 99%.

[0197] Example 25 Synthesis of 9β,10α-5,7-dehydroprogesterone diethyl ketal

[0198] The operation is as in Example 11, the illumination method is method C, and other conditions are as in the following table:

[0199]

[0200] The yield of 9β,10α-5,7-dehydroprogesterone diethyl ketal is 83.3%, and the liquid phase purity is more than 99%.

[0201] Example 26 Synthesis of 9β,10α-7-dehydroprogesterone

[0202] Dissolve 50g of 9β,10α-5,7-dehydroprogesterone diethyl ketal in a mixture of 400mL of acetone and 100mL of water, add 1mL of concentrated sulfuric acid, heat to 45℃-50℃, react for 1h, monitor the complete reaction of the raw material and the intermediate, cool down, neutralize with sodium bicarbonate solution, precipitate solid, filter, rinse with water, and dry under reduced pressure at 40℃ to constant weight to obtain 9β,10α-7-dehydroprogesterone with liquid phase purity>99% and yield of 97.3%. 1 H-NMR as attached Figure 4 shown.

[0203] Example 27 Synthesis of 9β,10α-7-dehydroprogesterone

[0204] Dissolve 500 g of 9β,10α-5,7-dehydroprogesterone diethylene acetal in a mixture of 4 L of methanol and 1 L of water, add 5 g of p-toluenesulfonic acid, raise the temperature to 40°C-45°C, react for 2 hours, monitor the complete reaction of the raw material and the intermediate, cool down, neutralize with sodium bicarbonate solution, precipitate solid, filter, rinse with water, and dry under reduced pressure at 40°C to constant weight to obtain 9β,10α-7-dehydroprogesterone with liquid phase purity >98.5% and a yield of 96.2%.

[0205] Example 28 Synthesis of 9β,10α-7-dehydroprogesterone

[0206] Dissolve 200 g of 9β,10α-5,7-dehydroprogesterone diethylene acetal in a mixture of 1.6 L of ethanol and 0.4 L of water, add 4 g of aminosulfonic acid, raise the temperature to 30°C-35°C, react for 3 hours, monitor the complete reaction of the raw material and the intermediate, cool down, neutralize with sodium bicarbonate solution, precipitate solid, filter, rinse with water, and dry under reduced pressure at 45°C to constant weight to obtain 9β,10α-7-dehydroprogesterone with liquid phase purity >98.5% and a yield of 97.6%.

[0207] Example 29 Synthesis of Dydrogesterone

[0208] Dissolve 30 g of 9β,10α-7-dehydroprogesterone in 300 mL of N,N-dimethylformamide, add 0.5 N zinc chloride, heat to 35°C-40°C and react for 4 h. When the remaining raw material is less than 0.5% by HPLC monitoring, stop the reaction, neutralize with sodium bicarbonate solution, add DCM for extraction, evaporate the solvent, and wash with 300 mL of acetonitrile at 10°C-15°C for 1 h-4 h, filter, rinse, and dry to obtain 22.1 g of crude dydrogesterone with a yield of about 73.7%. 1 H-NMR as attached Figure 5 shown.

[0209] Example 30 Synthesis of Dydrogesterone

[0210] 50 g of 9β,10α-7-dehydroprogesterone was dissolved in N,N-dimethylacetamide, and a mixture of 0.2 N zinc iodide and 0.3 N manganese (III) acetylophenone was added, and the mixture was reacted at 55°C-60°C for 2h-3h. When the remaining raw material was less than 0.5% by HPLC monitoring, the reaction was stopped, and the mixture was neutralized with sodium bicarbonate solution. DCM was added for extraction, and the solvent was evaporated and washed with 400 mL of acetone at 0°C for 2h, filtered, rinsed, and dried to obtain 39.3 g of crude dydrogesterone with a yield of about 78.5%.

[0211] Example 31 Synthesis of Dydrogesterone

[0212] Dissolve 100 g of 9β,10α-7-dehydroprogesterone in dimethyl sulfoxide, add 0.25 N aluminum triacetylacetonate, react at 70°C-75°C for 2 h, and when the remaining raw material is less than 0.5% as monitored by HPLC, stop the reaction, neutralize with sodium bicarbonate solution, add DCM for extraction, evaporate the solvent, and wash with 800 mL of methanol at -10°C for 1 h, filter, rinse, and dry to obtain 77.3 g of crude dydrogesterone with a yield of about 77.3%.

[0213] Example 32 Synthesis of Dydrogesterone

[0214] 30 g of 9β,10α-7-dehydroprogesterone was dissolved in N-methylpyrrolidone, 0.25 N copper acetate was added, and the mixture was reacted at 45°C-50°C for 4 h. When the remaining raw material was less than 0.5% as monitored by HPLC, the reaction was stopped, and the mixture was neutralized with sodium bicarbonate solution. DCM was added for extraction, and the solvent was evaporated and washed with 300 mL of isopropanol at 10°C for 1.5 h. The mixture was filtered, rinsed, and dried to obtain 20.8 g of crude dydrogesterone with a yield of about 69.3%.

[0215] Example 33 Synthesis of Dydrogesterone

[0216] Dissolve 50 g of 9β,10α-7-dehydroprogesterone in tetrahydrofuran, add 0.2N vanadium diacetylacetonate oxide, react at 65°C for 6 h, and when the remaining raw material is less than 0.5% as monitored by HPLC, stop the reaction, neutralize with sodium bicarbonate solution, add DCM for extraction, evaporate the solvent, and wash with a mixture of 200 mL of dichloromethane and 300 mL of n-hexane at -20°C for 1 h, filter, rinse, and dry to obtain 37.8 g of crude dydrogesterone with a yield of about 75.5%.

[0217] Example 34 Synthesis of Dydrogesterone

[0218] 50 g of 9β,10α-7-dehydroprogesterone was dissolved in toluene, and 0.3 N zirconium acetylacetonate and 0.1 N trimethylsilyl iodide were added. The mixture was reacted at 75° C. for 2 h. When the remaining raw material was less than 0.5% as monitored by HPLC, the reaction was stopped and the mixture was neutralized with sodium bicarbonate solution. DCM was added for extraction, and the solvent was evaporated and washed with 400 mL of acetone at 10° C. for 1 h. The mixture was filtered, rinsed, and dried to obtain 40.1 g of crude dydrogesterone with a yield of about 80.2%.

[0219] Example 35 Synthesis of Dydrogesterone

[0220] 30 g of 9β,10α-7-dehydroprogesterone was dissolved in acetonitrile, 0.5 N iodine was added, and the mixture was reacted at 45°C for 4 h. When the remaining raw material was less than 0.5% as monitored by HPLC, the reaction was stopped, and the mixture was neutralized with sodium bicarbonate solution. DCM was added for extraction, and the solvent was evaporated and washed with 300 mL of isopropanol at 10°C for 2 h. The mixture was filtered, rinsed, and dried to obtain 23.7 g of crude dydrogesterone with a yield of about 79.1%.

[0221] Example 36 Synthesis of Dydrogesterone

[0222] Dissolve 50 g of 9β,10α-7-dehydroprogesterone in dimethyl sulfoxide, add 0.3 N trimethylsilyl iodide, react at 60° C. for 6 h, and when the remaining raw material is less than 0.5% as monitored by HPLC, stop the reaction, neutralize with sodium bicarbonate solution, add DCM for extraction, evaporate the solvent, wash with 500 mL of acetone at 0° C. for 2 h, filter, rinse, and dry to obtain 37.3 g of crude dydrogesterone with a yield of about 74.5%.

[0223] Example 37 Synthesis of Dydrogesterone

[0224] Dissolve 30 g of 9β,10α-7-dehydroprogesterone in isopropanol, add 0.2 N zinc acetate and 0.2 N iodine, react at 30°C for 4 h, and when the remaining raw material is less than 0.5% as monitored by HPLC, stop the reaction, neutralize with sodium bicarbonate solution, add DCM for extraction, evaporate the solvent, wash with 240 mL of isopropanol at -10°C for 4 h, filter, rinse, and dry to obtain 24.4 g of crude dydrogesterone with a yield of about 81.3%.

[0225] Example 38 Synthesis of Dydrogesterone

[0226] Dissolve 10 g of 9β,10α-7-dehydroprogesterone in a mixture of dimethyl sulfoxide and acetonitrile, add 0.5 N potassium iodide and 0.2 N vanadium diacetylacetonate, react at 25° C. for 8 h, and when the remaining raw material is less than 0.5% as monitored by HPLC, stop the reaction, neutralize with sodium bicarbonate solution, add DCM for extraction, evaporate the solvent, and wash with 80 mL of acetone at -10° C. for 2 h, filter, rinse, and dry to obtain 7.86 g of crude dydrogesterone with a yield of about 78.6%.

[0227] Example 39: Purification of Dydrogesterone

[0228] 100 g of crude dydrogesterone was dissolved in 1 L of isopropanol, heated to reflux temperature for dissolution, and slowly cooled to -10°C to precipitate a white solid. The mixture was stirred for 2 h, filtered, washed, and dried under reduced pressure at 40°C to constant weight to obtain pure dydrogesterone with a purification yield of 87.4%.

[0229] Example 40 Purification of Dydrogesterone

[0230] Dissolve 50 g of crude dydrogesterone in 400 mL of ethanol, heat to reflux temperature to dissolve, slowly cool to -15°C, precipitate a white solid, continue stirring for 2 h, filter, rinse, and dry at 50°C under reduced pressure to constant weight to obtain pure dydrogesterone with a purification yield of 88.5%.

[0231] Example 41 Purification of Dydrogesterone

[0232] 50 g of crude dydrogesterone was dissolved in a mixture of 100 mL of ethylene glycol dimethyl ether and 300 mL of n-heptane, heated to reflux temperature for dissolution, slowly cooled to -15°C, a white solid precipitated, and stirred for 2 h. The mixture was filtered, washed, and dried at 50°C under reduced pressure to constant weight to obtain pure dydrogesterone with a purification yield of 92.3%.

[0233] Example 42 Purification of Dydrogesterone

[0234] 50 g of crude dydrogesterone was dissolved in 1.2 L of acetonitrile, heated to reflux temperature for dissolution, slowly cooled to -10°C, a white solid precipitated, and stirred for 2 h. The mixture was filtered, washed, and dried at 50°C under reduced pressure to constant weight to obtain pure dydrogesterone with a purification yield of 91.1%.

[0235] The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A method for preparing a dydrogesterone precursor compound e, comprising the following steps 4: adding compound d, solvent D, a photocatalyst, and an inhibitor into a photoreactor, adjusting the temperature of the reaction liquid to -20°C to 30°C, and performing a photochemical reaction to obtain compound e; in, does not exist or is a single bond; X is selected from halogen, such as Br or Cl; when When not present, R1 and R2 are the same or different and are independently selected from C 1-6 Alkyl; for example, methyl; when When it is a single bond, R1 and R2 are the same or different and are independently selected from C 1-6 Alkylene; for example, methylene; The photochemical reaction is selected from one of the following methods A, B or C: Method A: adjust the temperature of the reaction solution to -20°C to 30°C, turn on light source A for 2h-4h, turn off light source A, turn on light source B for 6h-8h, turn off light source B, and repeat 3 times; Method B: adjust the temperature of the reaction solution to -20°C to 30°C, turn on light source C for 4h-6h, then turn on light source D for 16h-20h, turn off light source C, and turn off light source D after 4h-6h; Method C: adjust the temperature of the reaction solution to -20°C to 30°C, turn on light source E for 20h-24h, turn off light source E, turn on light source F for 4h-6h, and turn off light source F; The solvent D is selected from hydrocarbon solvents, ether solvents, alcohol solvents, and ester solvents; preferably, the solvent D is selected from one or more of n-hexane, n-heptane, isooctane, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methanol, ethanol, isopropanol, and ethyl acetate; more preferably, the solvent D is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, ethyl acetate, isooctane, ethanol, and methanol; The photocatalyst is selected from 5,10-di(2-naphthyl)-5,10-dihydrophenazine, 1,2,4,5-tetracyanobenzene, 10-phenyl-10H-phenothiazine, anthraquinone, 1,8-dihydroxyanthraquinone, 1,4,5,8-tetrachloroanthraquinone, 9,10-dinitrile anthracene, 2-isopropylthioxanthone, 2-chloro-9-thioxanthone, 2-iodo-9-thioxanthone, 1,4-dinitrile naphthalene, 1 , 4-dichloronaphthalene, quinoxaline, 2,3-dihydroxyquinoxaline, 2,3-dichloroquinoxaline, one or more thereof; preferably, the photocatalyst is selected from 1,4,5,8-tetrachloroanthraquinone, 1,4-dinitrile naphthalene, 2,3-dihydroxyquinoxaline, 1,4-dichloronaphthalene, 9,10-dinitrile anthracene, 2-isopropylthioxanthone, 2-iodo-9-thioxanthone, quinoxaline, 1,8-dihydroxyanthraquinone The polymerization inhibitor is selected from one or more of 2,6-dimethyl-4-tert-butylphenol, hydroquinone, 1,4-naphthalene diol, and 5,8-dihydroxy-1,4-naphthoquinone; The wavelength of the light source A is selected from 225-345 nm, for example 245-325 nm, such as 245 nm, 254 nm, 265 nm, 275 nm, 295 nm, 305 nm, 315 nm, 325 nm, or a combination of several wavelengths; The wavelength of the light source B is selected from 250-360 nm, for example, 275-340 nm, such as 275 nm, 295 nm, 305 nm, 315 nm, 325 nm, 335 nm, 340 nm, or a combination of several wavelengths; The wavelength of the light source C is selected from 225-315 nm, for example, 245-295 nm, such as one or a combination of 245 nm, 254 nm, 265 nm, 275 nm, 295 nm; The wavelength of the light source D is selected from 315-360nm, for example, 295-340nm, such as 295nm, 305nm, 315nm, 325nm, 335nm, 340nm, or a combination of several wavelengths; The wavelength of the light source E is selected from 234-335 nm, for example, 254-315 nm, such as 254 nm, 265 nm, 275 nm, 285 nm, 295 nm, 305 nm, 315 nm, or a combination of several wavelengths; The wavelength of the light source F is selected from 285-360 nm, for example, 305-340 nm, such as one or a combination of 305 nm, 315 nm, 325 nm, 335 nm, 340 nm.

2. The preparation method according to claim 1, characterized in that: Step 4 also includes purification steps 4-2 to 4-4: 4-2: After the reaction is completed, the reaction solution is evaporated to remove the solvent, and the residue is washed with solvent D1 at -10°C to 50°C for 0.5h-1h, and filtered to obtain D1 filtrate and D1 filter residue, which can be recovered as raw material compound d; 4-3: After the solvent is evaporated from the D1 filtrate in step 4-2, the mixture is washed with solvent D2 at -10°C to 50°C for 0.5h-1h, and filtered to obtain D2 mother liquor and crude compound e; 4-4: Recrystallize the crude compound e with solvent D3 to obtain D3 mother liquor and purified compound e.

3. The preparation method according to claim 1 or 2, characterized in that: In step 4, the purification step further includes steps 4-5: 4-5: After mixing the mother liquor of D2 and the mother liquor of D3, the solvent is evaporated to recover the ring-opening intermediate, which is then combined with the recovered raw material compound d, and the process is repeated from step 4 using it as a substitute for the raw material.

4. The preparation method according to any one of claims 1 to 3, characterized in that In the step 4-2, the solvent D1 is selected from one or more of acetonitrile, acetone, methanol, ethanol, isopropanol, n-hexane, and ethyl acetate; In the step 4-3, the solvent D2 is selected from one or more of acetonitrile, acetone, methanol, ethanol, isopropanol, n-hexane, and dichloromethane; In step 4-4, the solvent D3 is selected from one or more of acetonitrile, acetone, butanone, methanol, ethanol, isopropanol, n-hexane, n-heptane, dichloromethane, and ethyl acetate.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The preparation method of the compound d comprises the following steps: in, X, R1, and R2 have the meanings as defined in any one of claims 1 to 4; Step 1: Compound a (progesterone) reacts with compound a1 to obtain compound b; compound a1 is selected from R1-OH, R2-OH and / or Step 2: Compound b reacts with a halogenating agent to obtain compound c; Step 3: Compound c undergoes elimination reaction to obtain compound d.

6. The preparation method according to any one of claims 1 to 5, characterized in that: Step 1 is carried out in the presence of a catalyst A, wherein the catalyst A is selected from one or more of sulfuric acid, aminosulfonic acid, concentrated hydrochloric acid, oxalyl chloride, acetyl chloride, and trifluoroacetic acid; Preferably, step 2 is carried out in the presence of an acid-binding agent, wherein the acid-binding agent is selected from one or more of pyridine, 4-methylpyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, potassium carbonate, and sodium carbonate; Preferably, in step 2, the halogenating agent is selected from one or more of N-bromosuccinimide, dibromohydantoin, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, N-chlorosuccinimide, and dichlorohydantoin; Preferably, step 3 is carried out in the presence of an organic base A, wherein the organic base A is selected from one or more of 2,6-lutidine, 2,4,6-trimethylpyridine, triethylamine, and diisopropylethylamine.

7. A method for preparing a dydrogesterone compound g, comprising the following steps: in, R1 and R2 have the definitions as described in claim 1; step 4 is according to the preparation method as described in claim 1; Step 4: Add compound d, solvent D, photocatalyst, and polymerization inhibitor into a photoreactor, adjust the temperature of the reaction solution to -20°C to 30°C, and perform a photochemical reaction to obtain compound e; Step 5: Compound e is subjected to a deprotection reaction to obtain compound f; Step 6: Compound f undergoes double bond isomerization reaction to obtain compound g.

8. The preparation method according to claim 7, characterized in that: Step 5 is carried out in the presence of a catalyst B, wherein the catalyst B is selected from one or more of sulfuric acid, sodium bisulfate, p-toluenesulfonic acid, aminosulfonic acid, hydrochloric acid, and phosphoric acid; Preferably, step 6 is carried out in the presence of a catalyst C, wherein the catalyst C is selected from one or more of zinc chloride, manganese chloride, ferrous chloride, cupric acetate, potassium iodide, sodium iodide, lithium bromide, cobalt chloride, zinc acetate, titanium trichloride, zinc iodide, manganese (III) acetylacetonate, manganese (III) acetyphenacetonate, aluminum triacetylacetonate, vanadium diacetylacetonate oxide, zirconium acetylacetonate, trimethylsilyl iodide, and iodine. Preferably, step 6 is carried out in the presence of a solvent F, wherein the solvent F is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, n-heptane, toluene, acetonitrile, acetone, methanol, ethanol, isopropanol, and water.

9. The preparation method according to claim 7 or 8, characterized in that: Step 6 also includes a purification step: after the reaction is completed, neutralize with sodium bicarbonate solution, extract to obtain an organic phase, evaporate the solvent of the organic phase, dissolve the residue with solvent F1, stir and wash at -10°C-80°C for 1h-4h, and filter to obtain the compound g; The solvent F1 is selected from one or more of acetonitrile, acetone, methanol, ethanol, isopropanol, n-hexane, petroleum ether and dichloromethane.

10. The preparation method according to any one of claims 7 to 9, characterized in that: The preparation method further comprises the step of refining compound g: Step 7: dissolving the compound g obtained in step 6 in solvent G, heating to reflux temperature to dissolve, cooling to -15°C to 25°C, precipitating a white solid, filtering to obtain a purified compound g; The solvent G is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, ethylene glycol monomethyl ether, cyclohexane, n-heptane, isooctane, and petroleum ether.

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