CN102964419A - Preparation method of compound dienogest - Google Patents
Preparation method of compound dienogest Download PDFInfo
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- CN102964419A CN102964419A CN2012105293940A CN201210529394A CN102964419A CN 102964419 A CN102964419 A CN 102964419A CN 2012105293940 A CN2012105293940 A CN 2012105293940A CN 201210529394 A CN201210529394 A CN 201210529394A CN 102964419 A CN102964419 A CN 102964419A
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Abstract
The invention discloses a preparation method of compound dienogest, comprising the following steps of: reacting a compound steroidal estrogens-5(10),9(11)-diene-3,17-diketone-3,3-ethylidene ketal serving as a raw material with cyanmethyl lithium obtained by reacting acetonitrile with n-butyl lithium at the reaction temperature of -50 DEG C to -35 DEG C; thus obtaining a compound 17alpha-cyanmethyl-17beta-hydroxy-5(10),9(11)-steroidal estrogens diene-3,17-diketone-3,3-ethylidene ketal; carrying out deprotection transposition to obtain 17alpha-cyanmethyl-17beta-hydroxy-13beta-methylsterane-4,9-diketone-3-ketone; and refining to obtain a dienogest high-quality product. The preparation method disclosed by the invention has the advantages of very simple route, novelty, easily available and cheap raw materials, low cost, no-toxic or low-toxic raw materials, short synthetic route, moderate conditions, easiness for operation, stability for amplification and high yield, and can be suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, be specifically related to a kind of preparation method of compound dienogest.
Background technology
Dienogest (Dienogest) is a kind of mixing progestogen.Nineteen ninety-five, dienogest and ethinylestradiol compound preparation (2mg+0.03mg) go on the market in Germany as contraceptive bian, and 2007 at Australia's listing, trade(brand)name Valette.It has synthetic and mixes the pharmacological characteristic of progestogen and the double properties with 19-norepinephrine testosterone derivative, has simultaneously very high progestin, its endocrine pharmacology characteristic is ideal, no estrogen, estrogen antagonist and androgenic activity, the antigonadotropic effect is also very weak, also has certain androgen antagonist activity.
As far back as eighties of last century seventies, the synthetic of a lot of scholar's research dienogests just arranged, therefore up to the present, the synthetic document of dienogest is more, mainly contains following several synthetic routes:
US Patent No. 4167517 (1979), US 4248790 (1981) are take Estrone-3-methyl ether as starting raw material, and through reduction, cyaniding is hydrolyzed, and upper bromine debrominate obtains dienogest; Concrete synthetic route is as follows:
This route is first with 17 ketone group cyaniding open loops, after with 3 methyl ether hydrolysis.But there is shortcomings in this route, and at first Estrone-3-methyl ether obtains formula (2) through the Birch reduction, and yield is low, severe reaction conditions, and bromine debrominate impurity is higher in the final step, needs column chromatography and recrystallization just can obtain the high dienogest of purity, and yield is very low; In reaction process, to use highly toxic product potassium cyanide in addition.
The route of synthetic dienogest is as follows among the patent WO 2007066158A2:
In this reaction scheme, use the oxalic acid hydrolysis to obtain compound (4), in the aftertreatment water washing process, washing times is many, and all unstable to alkali to acid, and yield is low; After obtaining the dienogest crude product, need column chromatography, whole operational path is longer, and after attempting experiment, overall yield less than 18% is difficult for realizing suitability for industrialized production.
The people such as Vrijhof applied for a patent EP 07769904A2 in 1997, the route of its synthetic dienogest is as follows:
In this reaction scheme, take triethyl orthoformate and propylene glycol as raw material, under the catalysis of tosic acid, the mode of 3 ketone groups with ketal protected, can make the anti-highly basic of compound (2), improve 17 epoxidation efficient; Epoxidation makes formula (3), and the cyaniding open loop obtains formula (4), but the prices such as trimethylsulfonium iodine are expensive, and the epoxidation yield is low, and the potassium cyanide severe toxicity is not suitable for industrialized production.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of compound dienogest, and it goes for industrialized production.
For solving the problems of the technologies described above, the preparation method's of the compounds of this invention dienogest technical solution is:
With compound female steroid-5(10), 9 (11)-diene-3,17-diketone-3,3-ethylidene ketone acetal is raw material, with reacted the reaction of resulting cyanogen lithium methide by acetonitrile and n-Butyl Lithium, obtain compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal; Carry out the deprotection transposition again, obtain 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone gets the dienogest elaboration after making with extra care; Synthetic route is as follows:
。
Described preparation method may further comprise the steps:
Step 1, with raw material female steroid-5(10), 9 (11)-diene-3,17-diketone-3,3-ethylidene ketone acetal (formula 1) and cyanogen lithium methide react to get compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2);
Step 2, with compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3, protection is gone in 3-ethylidene ketone acetal (formula 2) acidolysis, get compound 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3), i.e. dienogest crude product;
Step 3, with compound 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3) crude product namely gets the dienogest elaboration through simple recrystallization.
The reaction solvent of described step 1 is one or more in methylene dichloride, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), acetonitrile, toluene, methyl alcohol, the ethanol, preferred tetrahydrofuran (THF).
Described cyanogen lithium methide is made by acetonitrile and n-Butyl Lithium reaction.
The reaction solvent of described step 2 is one or more in acetic acid, tetrahydrofuran (THF), ether, isopropyl ether, acetonitrile, chloroform or the methylene dichloride, particular methanol or acetic acid.
The simple recrystallization solvent for use of described step 3 is ethyl acetate, acetonitrile, acetone, ethanol, methyl alcohol, water or their arbitrary combination, preferred acetonitrile or methyl alcohol.
Described preparation method may further comprise the steps:
The first step prepares 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2);
Tetrahydrofuran (THF) is dropped in the reaction flask, cool to below-40 ℃, add n-butyllithium solution, drip the mixing solutions of acetonitrile and tetrahydrofuran (THF), generate the cyanogen lithium methide; Stir after 15 minutes, drip again raw material female steroid-5(10), 9 (11)-diene-3,17-diketone-3, the mixing solutions of 3-ethylidene ketone acetal (formula 1) and tetrahydrofuran (THF), temperature is controlled between-80～-20 ℃, stirred 0.5 hour, the rear dropping water termination reaction that reacts completely is divided and is got organic layer, washing obtains compound formula (2) after dehydration is concentrated;
Second step, preparation compound 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3);
With compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2) is used dissolution with solvents, drip acid in reaction flask, under 15～40 ℃, deprotection and transposition are after reacting completely, elutriation or concentrated rear elutriation, filter, washing namely gets the dienogest crude product;
The 3rd step, preparation dienogest elaboration;
With the dienogest crude product with acetonitrile or dissolve with methanol, activated carbon decolorizing, recrystallization gets the dienogest elaboration for several times.
Drip reacting temperature in the described the first step is-80～-20 ℃, preferred-50～-30 ℃.
Used deprotection transposition reagent is one or more of perchloric acid, concentrated hydrochloric acid, dilute sulphuric acid, acetic acid or trifluoracetic acid, tosic acid or hydrogen chloride gas in the described second step.
The technique effect that the present invention can reach is:
The present invention is with female steroid-5(10), 9 (11)-diene-3,17-diketone-3,3-ethylidene ketone acetal is starting raw material, the termination reaction water, cyanogenation through 17, then 3 deprotections, △ 6(10), 11(9) two key transpositions, namely get the dienogest crude product, content (HPLC) is more than 70%, and the crude product yield reaches more than 95%; Through the several recrystallization, content (HPLC) can be up to more than 99.7%, and maximum contaminant is below 0.1%, and total recovery more than 40% is very easily taken pharmaceutical prod.The present invention is convenient succinct, and used raw material is cheap in the reaction process, and yield is high, is adapted to industrialized production.Be in particular in following some:
1, directly go up the cyanogen methyl for 17, avoided patent US4167517(1979), US4248790(1981), EP07769904A2(1997) in upper cyanogen method of two steps;
2, when △ 3 deprotection, simultaneously with △-5(10), 9(11) the diene transposition becomes △-4(5), 9(10) diene has been avoided the two-step approach among the patent WO2007066158A, namely takes off △ 3 protecting groups with oxalic acid and with bromine debrominate on the pyridinium tribromide, generation △-4(5), 9(10) diene; Reaction from formula (1) to the crude product yield about 95%, HPLC is 70%;
3, the present invention is in tetrahydrofuran (THF), generates the cyanogen lithium methide with acetonitrile and n-Butyl Lithium reaction, and 17 ketone groups with formula (2) react upper 17 α cyanogen methyl and 17 β hydroxyls again; Reactant purity HPLC is more than 96%; After sour deprotection transposition, elutriation obtains the dienogest crude product, and yield can reach more than 95%; Content in crude product reaches more than 70%, and by decolorizing and refining, total recovery is more than 40% again, and HPLC is that maximum contaminant is below 0.1% more than 99.7%;
4, route of the present invention is very simple and direct, novelty, and raw material is easy to get and is inexpensive, and cost is low, raw materials used nontoxic or low toxicity, synthetic route is short, mild condition, easy handling amplifies and stablizes, and yield is high, can be applicable to industrialized production.
The present invention is further detailed explanation below in conjunction with embodiment:
Embodiment
The preparation method of the compounds of this invention dienogest may further comprise the steps:
The first step prepares 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2);
Tetrahydrofuran (THF) is dropped in the reaction flask, cool to below-40 ℃, add n-butyllithium solution, drip the mixing solutions of acetonitrile and tetrahydrofuran (THF), stir after 15 minutes, drip again raw material female steroid-5(10), 9 (11)-diene-3,17-diketone-3, the mixing solutions of 3-ethylidene ketone acetal (formula 1) and tetrahydrofuran (THF), temperature are controlled between-80～-20 ℃, preferred-50～-30 ℃, stirred 0.5 hour, drip again the water termination reaction after reacting completely, divide and get organic layer, washing, obtain compound formula (2) after dehydration is concentrated, purity is more than 96%;
Second step prepares 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3) dienogest crude product;
Compound formula (2) is used dissolution with solvents, under 15～40 ℃, acid adding deprotection and transposition, after reacting completely, elutriation or be concentrated into small volume after elutriation, filter, washing namely gets the dienogest crude product, purity is more than 70%;
The solvent of dissolution type (2) can be one or more in acetic acid, methylene dichloride, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), acetonitrile, toluene, methyl alcohol, the ethanol;
Added acid can be one or more of perchloric acid, concentrated hydrochloric acid, dilute sulphuric acid, acetic acid or trifluoracetic acid, tosic acid or hydrogen chloride gas;
The 3rd step, preparation dienogest elaboration;
With dienogest crude product dissolution with solvents, activated carbon decolorizing, the several recrystallization, can get off-white color solid 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3), the dienogest purity is more than 99.7%, and maximum contaminant content is below 0.1%, yield can reach more than 40%, is fit to suitability for industrialized production;
The solvent of dissolving dienogest crude product can be ethyl acetate, acetonitrile, acetone, ethanol, methyl alcohol, water or their arbitrary combination;
The dienogest synthetic route is as follows:
Embodiment 1: prepare 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2)
In the four-hole boiling flask of 3L, add the 450ml tetrahydrofuran (THF), cool to below-50 ℃, slowly add n-butyllithium solution 525ml, exothermic heat of reaction, stirring and adjusting temperature drip the mixing solutions of 300ml tetrahydrofuran (THF) and 130ml acetonitrile between-80～-20 ℃, drip and finish, stirred 15 minutes; With the tetrahydrofuran (THF) of 900ml drying dissolving 148 gram female steroids-5(10), 9 (11)-diene-3,17-diketone-3,3-ethylidene ketone acetal (formula 1) is added drop-wise in the reaction flask between-80～-20 ℃, drips to finish, stirred 0.5 hour, temperature adjustment drips 400ml water below-40 ℃, stirred 1 hour, static layering is collected organic phase, organic phase is dewatered with 800ml washing twice, is evaporated to dried under 40 ℃, get an oily matter (being compound formula 2), purity (HPLC) 96%.
Embodiment 2: prepare 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3) crude product
17 alfa-cyanomethyls-17 beta-hydroxy-5(10) is being housed, 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2) is by adding methyl alcohol 200ml in the 1000ml reaction flask of formula (1) 48 gram, stirring and dissolving is under room temperature, add hydrochloric acid 10ml, stirred 1.5 hours, 40 ℃ are concentrated into elutriation behind the small volume, filter, washing, obtain yellow solid 48 grams, be the dienogest crude product, purity (HPLC) is 70%.
Embodiment 3: prepare 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3) crude product
17 alfa-cyanomethyls-17 beta-hydroxy-5(10) is being housed, 9 (11)-estradienes-3,17-diketone-3, add methyl alcohol 200ml in the reaction flask of 3-ethylidene ketone acetal (formula 2) by the 1000ml of formula (1) 48 gram, stirring and dissolving is under room temperature, add tosic acid 10 grams, stirred 18 hours, 40 ℃ are concentrated into elutriation behind the small volume, filter, washing, obtain yellow solid 47 grams, be the dienogest crude product, purity (HPLC) is 71.5%.
Embodiment 4: prepare 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3) crude product
17 alfa-cyanomethyls-17 beta-hydroxy-5(10) is being housed, 9 (11)-estradienes-3,17-diketone-3, add acetic acid 200ml in the reaction flask of 3-ethylidene ketone acetal (formula 2) by the 1000ml of formula (1) 48 gram, stirring and dissolving, under room temperature, add sulfuric acid 10ml, stirred 1.5 hours; Elutriation filters, and washing obtains yellow solid 46 grams, is the dienogest crude product, and purity (HPLC) is 70.5%.
Embodiment 5: preparation dienogest elaboration;
Dienogest crude product 48 grams with the acetonitrile dissolving, are added activated carbon decolorizing, and recrystallization 5 times gets off-white color crystallization 21 grams, yield 43.75%, purity (HPLC) 99.7%, maximum contaminant 0.06%.
Embodiment 6: preparation dienogest elaboration;
Dienogest crude product 47 grams are used dissolve with methanol, activated carbon decolorizing, recrystallization 4 times gets off-white color crystallization 20 grams, yield 42.55%, purity (HPLC) 99.8%, maximum contaminant 0.061%.
Embodiment 7: preparation dienogest elaboration;
Dienogest crude product 46 grams are used acetone solution, activated carbon decolorizing, recrystallization 3 times is used recrystallizing methanol 2 times again, gets elaboration 19 grams, yield 41.3%, purity (HPLC) 99.9%, maximum contaminant 0.05%.
Claims (9)
1. the preparation method of a compound dienogest, it is characterized in that: with compound female steroid-5(10), 9 (11)-diene-3,17-diketone-3,3-ethylidene ketone acetal is raw material, and is reacted the reaction of resulting cyanogen lithium methide by acetonitrile and n-Butyl Lithium, obtain compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal; Carry out the deprotection transposition again, obtain 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone gets the dienogest elaboration after making with extra care; Synthetic route is as follows:
2. the preparation method of compound dienogest according to claim 1 is characterized in that, described preparation method may further comprise the steps:
Step 1, with raw material female steroid-5(10), 9 (11)-diene-3,17-diketone-3,3-ethylidene ketone acetal (formula 1) and cyanogen lithium methide react to get compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2);
Step 2, with compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3, protection is gone in 3-ethylidene ketone acetal (formula 2) acidolysis, get compound 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3), i.e. dienogest crude product;
Step 3, with compound 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3) crude product namely gets the dienogest elaboration through simple recrystallization.
3. the preparation method of compound dienogest according to claim 2 is characterized in that, the reaction solvent of described step 1 is one or more in methylene dichloride, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), acetonitrile, toluene, methyl alcohol, the ethanol.
4. the preparation method of compound dienogest according to claim 2 is characterized in that, described cyanogen lithium methide is made by acetonitrile and n-Butyl Lithium reaction.
5. the preparation method of compound dienogest according to claim 2 is characterized in that, the reaction solvent of described step 2 is one or more in acetic acid, tetrahydrofuran (THF), ether, isopropyl ether, acetonitrile, chloroform or the methylene dichloride.
6. the preparation method of compound dienogest according to claim 2 is characterized in that, the simple recrystallization solvent for use of described step 3 is ethyl acetate, acetonitrile, acetone, ethanol, methyl alcohol, water or their arbitrary combination.
7. the preparation method of compound dienogest according to claim 1 is characterized in that, described preparation method may further comprise the steps:
The first step prepares 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2);
Tetrahydrofuran (THF) is dropped in the reaction flask, cool to below-40 ℃, under nitrogen protection, add n-butyllithium solution, drip the mixing solutions of acetonitrile and tetrahydrofuran (THF), generate the cyanogen lithium methide; Stir after 15 minutes, drip again raw material female steroid-5(10), 9 (11)-diene-3,17-diketone-3,3-ethylidene ketone acetal (formula 1), temperature is controlled between-80～-20 ℃, stirred 0.5 hour, the rear dropping water termination reaction that reacts completely is divided and is got organic layer, washing obtains compound formula (2) after dehydration is concentrated;
Second step, preparation compound 17 alfa-cyanomethyls-17 beta-hydroxy-13 Beta-methyl gonane-4,9-diene-3-ketone (formula 3) dienogest crude product;
With compound 17 alfa-cyanomethyls-17 beta-hydroxy-5(10), 9 (11)-estradienes-3,17-diketone-3,3-ethylidene ketone acetal (formula 2) is used dissolution with solvents, drip acid in reaction flask, under 15～40 ℃, deprotection and transposition are after reacting completely, elutriation or concentrated rear elutriation, filter, washing namely gets the dienogest crude product;
The 3rd step, preparation dienogest elaboration;
With the dienogest crude product with acetonitrile or dissolve with methanol, activated carbon decolorizing, recrystallization gets the dienogest elaboration for several times.
8. the preparation method of compound dienogest according to claim 7 is characterized in that, the drip reacting temperature in the described the first step is-80～-20 ℃.
9. the preparation method of compound dienogest according to claim 7; it is characterized in that used deprotection transposition reagent is one or more of perchloric acid, concentrated hydrochloric acid, dilute sulphuric acid, acetic acid or trifluoracetic acid, tosic acid or hydrogen chloride gas in the described second step.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357937A (en) * | 2018-03-26 | 2019-10-22 | 华润紫竹药业有限公司 | A kind of Dienogest compound |
| CN112209987A (en) * | 2020-09-28 | 2021-01-12 | 湖南新合新生物医药有限公司 | Preparation method of dienogest |
| CN112375122A (en) * | 2020-11-12 | 2021-02-19 | 湖南新合新生物医药有限公司 | Preparation method of dienogest and method for recovering dienogest from dienogest mother liquor |
| CN112724191A (en) * | 2020-12-30 | 2021-04-30 | 上海汇伦生物科技有限公司 | Refining method of dienogest |
| CN113387991A (en) * | 2020-03-13 | 2021-09-14 | 苏州朗科生物技术股份有限公司 | Method and compound for synthesizing dydrogesterone |
| CN115521352A (en) * | 2022-11-01 | 2022-12-27 | 湖南新合新生物医药有限公司 | Preparation method of methyl dienolone |
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| CN102718828A (en) * | 2011-03-30 | 2012-10-10 | 西藏海思科药业集团股份有限公司 | Preparation method for dienogest |
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| CN102718828A (en) * | 2011-03-30 | 2012-10-10 | 西藏海思科药业集团股份有限公司 | Preparation method for dienogest |
Non-Patent Citations (1)
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| DISCLOSED ANONYMOUSLY: "SYNTHESIS, PURIFICATION AND CRYSTALLINE FORM DATA OF DIENOGEST [17-CYANOMETHYL-17-HYDROXYESTRA-4,9-DIENE-3-ONE]", 《THE IP.COM PRIOR ART DATEBASE》, 24 October 2011 (2011-10-24) * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357937A (en) * | 2018-03-26 | 2019-10-22 | 华润紫竹药业有限公司 | A kind of Dienogest compound |
| CN113387991A (en) * | 2020-03-13 | 2021-09-14 | 苏州朗科生物技术股份有限公司 | Method and compound for synthesizing dydrogesterone |
| CN112209987A (en) * | 2020-09-28 | 2021-01-12 | 湖南新合新生物医药有限公司 | Preparation method of dienogest |
| CN112209987B (en) * | 2020-09-28 | 2021-12-14 | 湖南新合新生物医药有限公司 | Preparation method of dienogest |
| CN112375122A (en) * | 2020-11-12 | 2021-02-19 | 湖南新合新生物医药有限公司 | Preparation method of dienogest and method for recovering dienogest from dienogest mother liquor |
| CN112375122B (en) * | 2020-11-12 | 2024-02-02 | 湖南新合新生物医药有限公司 | Preparation method of dienogest and method for recovering dienogest from dienogest mother liquor |
| CN112724191A (en) * | 2020-12-30 | 2021-04-30 | 上海汇伦生物科技有限公司 | Refining method of dienogest |
| CN115521352A (en) * | 2022-11-01 | 2022-12-27 | 湖南新合新生物医药有限公司 | Preparation method of methyl dienolone |
| CN115521352B (en) * | 2022-11-01 | 2024-05-14 | 湖南新合新生物医药有限公司 | Preparation method of methyl dehydropregnenolone |
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