CN111944001A - Preparation method of tibolone - Google Patents
Preparation method of tibolone Download PDFInfo
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- CN111944001A CN111944001A CN202010655830.3A CN202010655830A CN111944001A CN 111944001 A CN111944001 A CN 111944001A CN 202010655830 A CN202010655830 A CN 202010655830A CN 111944001 A CN111944001 A CN 111944001A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
Abstract
The invention discloses a preparation method of tibolone, belonging to the technical field of preparation and processing of steroid hormone medicaments. The method takes 6, 7-didehydro norethindrone as a starting material, and tibolone is prepared by Grignard, diethanolation and hydrolysis reaction. The 7-methyl step is introduced in the Grignard reaction step in the synthetic route, the 17-hydroxyl is not required to be specially protected, the ratio of the 7 alpha-methyl intermediate and the 7 beta-methyl isomer obtained by the reaction is more than 20:1, chromatographic separation is not required, the required single 7 alpha-methyl intermediate can be obtained by simple treatment, the purification process is simple, the purity of the final product reaches more than 99.0 percent, and the yield is higher than 60 percent; the raw materials are cheap and easy to obtain, the reaction steps are few, the reaction conditions are mild and safe, and the control operation is easy; the reagent used in the reaction has little environmental pollution and good economic and social benefits.
Description
Technical Field
The invention relates to the technical field of preparation and processing of steroid hormone medicaments, in particular to a preparation method of tibolone.
Background
Tibolone (Tibolone), the chemical name is 17 beta-hydroxy-7 alpha-methyl-19-nor pregna-5 (10) -alkene-20-alkyne-3-ketone, have androgen activity and weak progestational hormone activity, have obvious anabolic effects, can prevent post-menopausal climacteric syndrome such as osteoporosis of women, lighten climacteric symptoms such as flushing, sweating and the like, belong to anabolic hormone and male hormone drugs, and are used for treating menopause and post-menopause syndrome.
Recl.Trav.Chim.Pays-Bas 105-111(1986) reports a tibolone synthesis method, which uses diester as a starting material to obtain a final product tibolone through Grignard, hydrolysis, oxidation, chromatographic separation, dealdehyding, 3-position protection, alkynylation and hydrolysis, wherein the synthesis route is as follows:
when the 7-methyl is formed by the method, the ratio of the 7 alpha-methyl to the 7 beta-methyl isomer is 4:1, the required 7 alpha-methyl intermediate can be obtained only by chromatographic separation, the cost is higher, the synthetic route has long steps and low overall yield, and the method is not beneficial to industrial production.
HELVETICA chimica acta 50,1453, 1453(1967) reports a tibolone synthesis method, which uses dehydroepiandrosterone as starting material, and obtains 7 alpha-methyl intermediate through 7 steps of reaction, and then obtains the final product tibolone through reduction, oxidation, alkynization and hydrolysis, wherein the synthesis route is as follows:
the synthesis method has the reaction steps as many as 11 steps, needs a lithium ammonia reagent in the reaction process, is not environment-friendly, has large potential safety hazard and low overall yield, and has the advantages that when 7-position methyl is introduced, the ratio of 7 alpha-methyl isomers to 7 beta-methyl isomers is 1.5:1, the purification is difficult, the equipment investment is huge, and the large-scale production is difficult to form.
CN110981930 reports a synthesis method of tibolone, which uses 19-nor-4-androstenedione as an initial raw material to obtain a final product tibolone through ethynylation, acylation, bromination, debromination, methylation, transposition and hydrolysis, wherein the synthesis route is as follows:
the synthesis method has more steps, the methylation reaction of the 17-position acetate in the methylation step of the process can also generate methylation reaction, more impurities can be generated, and the final hydrolysis step can lead the 17-position acetate to be difficult to hydrolyze under the acidic condition, thus leading the purification of the final product to be difficult, having low total yield and being not beneficial to industrial production.
Disclosure of Invention
In order to solve the problems of high raw material cost, long reaction route, difficult purification, low total yield and great pollution in the production process in the existing tibolone preparation process, the invention provides the tibolone preparation method which is simple in purification, high in yield and low in pollution.
The purpose of the invention is realized by the following steps:
a preparation method of tibolone comprises the following synthetic route:
the method specifically comprises the following steps:
1) and (3) performing a Grignard reaction: under the protection of inert gas, adding a metal catalyst and a methylation reagent into an organic solvent A, adding 6, 7-didehydro norethindrone (1) into the organic solvent A under the low-temperature stirring at the temperature of between 40 ℃ below zero and 20 ℃ below zero for reaction, after the thin-layer chromatography shows that the raw materials are completely converted, adding a reaction solution into an acid solution A, extracting the reaction solution with an organic solvent B, washing an organic layer with water to be neutral, concentrating, filtering and drying to obtain an intermediate (2);
2) double etherification reaction: under the protection of inert gas, adding the intermediate (2) obtained in the step 1) into methanol, adding an acid catalyst and a dehydrating agent, stirring and reacting at 20-50 ℃, adding an organic base after the thin-layer chromatography shows that the raw materials are completely converted, cooling to-20-0 ℃, and filtering to obtain an intermediate (3);
or
Adding the intermediate (2) obtained in the step 1) into an organic solvent C, adding methanol and an acidic catalyst, stirring, refluxing and dehydrating, adding an organic base after the thin-layer chromatography shows that the raw materials are completely converted, cooling to-20-0 ℃, and filtering to obtain an intermediate (3);
3) and (3) hydrolysis reaction: adding the intermediate (3) obtained in the step 2) into an organic solvent D, adding an acid solution B, stirring at 5-25 ℃ for reaction, adding an alkali solution for neutralization after the thin-layer chromatography shows that the raw materials are completely converted, adding water for elutriation, filtering to obtain a crude product, and refining the crude product once by using an organic solvent E to obtain tibolone.
Further, the organic solvent A in the step 1) is one of tetrahydrofuran, methyltetrahydrofuran or diethyl ether, and the volume dosage of the organic solvent A is 10-50 times of the weight of the substrate 6, 7-didehydro norethindrone (1); the metal catalyst is one of cuprous chloride, cupric chloride, cuprous bromide, cuprous iodide, cupric acetate or cuprous acetate, and the weight amount of the metal catalyst is 0.05-0.5 times of that of the substrate 6, 7-didehydro norethindrone (1); the methylation reagent is one of tetrahydrofuran or diethyl ether solution of methyl magnesium chloride, tetrahydrofuran or diethyl ether solution of methyl magnesium bromide and tetrahydrofuran or diethyl ether solution of methyl magnesium iodide, the molar concentration of the methylation reagent is 1-5 mol/L, and the molar amount of the methylation reagent is 3-10 times of that of the substrate 6, 7-didehydronorethindrone (1); the acid solution A is one of dilute sulfuric acid, dilute hydrochloric acid water solution or acetic acid water solution, the mass concentration of the acid solution A is 5-30%, and the volume consumption of the acid solution A is 15-40 times of the weight of the substrate 6, 7-didehydro norethindrone (1); the organic solvent B is one of dichloromethane, dichloroethane, ethyl acetate, toluene or n-butyl acetate, and the volume consumption of the organic solvent B is 5-30 times of the weight of the substrate 6, 7-didehydro-norethindrone (1).
Further, the volume dosage of the methanol in the step 2) is 1 to 15 times of the weight of the input intermediate (2); the acid catalyst is one of glacial acetic acid, malonic acid, p-toluenesulfonic acid, benzenesulfonic acid, pyridine hydrobromide or pyridine hydrochloride, and the weight amount of the acid catalyst is 0.01-0.2 times of the weight of the input intermediate (2); the dehydrating agent is one of Dicyclohexylcarbodiimide (DCC), boron trifluoride diethyl etherate, N-diisopropyl carbodiimide (DIC), N-Carbonyldiimidazole (CDI) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), and the weight amount of the dehydrating agent is 0.5-2 times of the weight of the input intermediate (2); the organic solvent C is one of toluene, xylene, cyclohexane, n-hexane, petroleum ether, octane or heptane, and the volume consumption of the organic solvent C is 5-30 times of the weight of the input intermediate (2); the organic base is pyridine or triethylamine, and the volume dosage of the organic base is 0.01 to 0.2 time of the weight of the input intermediate (2).
Further, in the step 3), the organic solvent D is one of methanol, ethanol, isopropanol, acetone, butyl ketone, tetrahydrofuran or methyl tetrahydrofuran, and the volume usage amount of the organic solvent D is 5-30 times of the weight of the input intermediate (3); the acid solution B is one of oxalic acid, formic acid, acetic acid, malonic acid or propionic acid aqueous solutions, the volume concentration of the acid solution B is 0.5-10%, and the volume dosage of the acid solution B is 5-30 times of the weight of the added intermediate (3); the alkali solution is one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium sulfite, potassium sulfite, sodium hydroxide or potassium hydroxide water solution, and the mass concentration of the alkali solution is 5-15%; the organic solvent E is at least one of acetone, butanone, methanol, ethanol, dichloromethane, isopropanol or dichloroethane.
Preferably, the inert gas is nitrogen or argon.
The invention has the technical characteristics and beneficial effects that:
1) the 7-methyl step is introduced in the Grignard reaction step in the synthetic route, no special protection is needed to be carried out on the 17-hydroxyl, the ratio of the 7 alpha-methyl intermediate obtained by the reaction to the 7 beta-methyl isomer is more than 20:1, the single 7 alpha-methyl intermediate can be extracted by simple refining treatment of crystallization and filtration in an organic solvent B without chromatographic separation, and the purification process is simple;
2) the amount of 7 beta-methyl isomer obtained by the reaction in the method is little, the purity of the final product reaches more than 99.0 percent, and the yield is higher than 60 percent;
3) the raw material 6, 7-didehydro norethindrone in the synthetic route is a derivative of norethindrone, and is widely available in the market and cheap and easily available;
4) the method has mild and safe reaction conditions (high-temperature and high-pressure reaction is not involved), is easy to control and operate, has few reaction steps (only three chemical reactions are needed), has less equipment investment and has extremely high market competitiveness on the production cost;
5) the reagent used in the preparation method of the invention has little environmental pollution and good economic and social benefits.
Detailed Description
The invention is further illustrated with reference to the following examples, which are not intended to limit the invention.
The procedures or conditions are not described in the examples, and the procedures can be performed according to the conventional experimental methods described in the publications in the field, and the reagents or equipment used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 preparation of tibolone
Step 1: adding 2.5g of cuprous chloride and 500ml of 1M tetrahydrofuran solution of methyl magnesium iodide into 500ml of tetrahydrofuran under the protection of nitrogen, adding 50g of 6, 7-didehydro-ynolone (1) into the tetrahydrofuran under stirring at the low temperature of-20 ℃ for reaction, adding the reaction solution into 750ml of 5% hydrochloric acid aqueous solution after the thin-layer chromatography shows that the raw materials are completely converted, adding 250ml of dichloromethane for extraction, washing an organic layer to be neutral, concentrating, filtering and drying to obtain 42.5g of intermediate (2);
step 2: under the protection of nitrogen, 42.5g of the intermediate (2) is added into 600ml of methanol, 0.5g of pyridine hydrobromide and 42.5g of boron trifluoride ether are added, stirring reaction is carried out at 40 ℃, after the thin-layer chromatography shows that the raw materials are completely converted, 8.5ml of triethylamine is added, the temperature is reduced to-10 ℃, and filtration is carried out, thus obtaining 34g of the intermediate (3);
and step 3: adding 34g of the intermediate (3) into 1000ml of methanol, adding 1000ml of 0.5% oxalic acid aqueous solution, stirring at 25 ℃ for reaction, after the thin-layer chromatography shows that the raw materials are completely converted, neutralizing with 5% sodium hydroxide aqueous solution, adding water for water precipitation, filtering to obtain a crude product, and refining the crude product with ethanol once to obtain 30.3g of tibolone. The total mass yield is 60.6 percent, and the product purity is 99.3 percent
EXAMPLE 2 preparation of tibolone
Step 1: adding 5g of copper chloride and 340ml of 3M diethyl ether solution of methyl magnesium bromide into 1500ml of diethyl ether under the protection of argon, adding 50g of 6, 7-didehydro norethindrone (1) into the mixture at the temperature of-30 ℃ under stirring for reaction, adding the reaction solution into 1500ml of 10% sulfuric acid aqueous solution after the raw materials are completely converted by thin-layer chromatography analysis, adding 1000ml of ethyl acetate for extraction, washing an organic layer with water until the organic layer is neutral, concentrating, filtering and drying to obtain 43.1g of an intermediate (2);
step 2: under the protection of nitrogen, 43.1g of the intermediate (2) is added into 400ml of methanol, 8g of malonic acid and 25g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) are added, stirring reaction is carried out at 20 ℃, after the thin layer chromatography shows that the raw materials are completely converted, 4.5ml of pyridine is added, the temperature is reduced to-20 ℃, and filtration is carried out, thus obtaining 34.3g of the intermediate (3);
and step 3: 34.3g of the intermediate (3) is added into 180ml of acetone, 200ml of 1% malonic acid aqueous solution is added, stirring reaction is carried out at 15 ℃, after TLC analysis shows that the raw material is completely converted, 15% sodium sulfite aqueous solution is used for neutralization, water is added for water precipitation, and filtration is carried out to obtain a crude product, and the crude product is refined once by dichloromethane and acetone to obtain 30.6g of tibolone. The total mass yield is 61.2 percent, and the product purity is 99.2 percent
EXAMPLE 3 preparation of tibolone
Step 1: under the protection of nitrogen, adding 330ml of tetrahydrofuran solution of 25g of copper acetate and 5M of methyl magnesium chloride into 2500ml of methyl tetrahydrofuran, adding 50g of 6, 7-didehydro-ynolone (1) into the mixture at the low temperature of-40 ℃ under stirring for reaction, after the thin-layer chromatography shows that the raw materials are completely converted, adding the reaction solution into 1200ml of 30% acetic acid aqueous solution, adding 1500ml of toluene for extraction, washing an organic layer to be neutral, concentrating, filtering and drying to obtain 42.7g of intermediate (2);
step 2: under the protection of nitrogen, 42.7g of the intermediate (2) is added into 50ml of methanol and 600ml of cyclohexane, 1.3g of benzenesulfonic acid is added, reflux dehydration and stirring reaction are carried out, after thin-layer chromatography analysis shows that the raw material is completely converted, 2ml of triethylamine is added, the temperature is reduced to 0 ℃, and filtration is carried out, so as to obtain 33.8g of the intermediate (3);
and step 3: adding 33.8g of the intermediate (3) into 500ml of tetrahydrofuran, adding 200ml of 10% acetic acid aqueous solution, stirring at 5 ℃ for reaction, neutralizing with 10% sodium carbonate aqueous solution after the thin-layer chromatography shows that the raw materials are completely converted, adding water for water precipitation, filtering to obtain a crude product, and refining the crude product once with isopropanol to obtain 30.1g of tibolone. The total mass yield is 60.2 percent, and the product purity is 99.3 percent
EXAMPLE 4 preparation of tibolone
Step 1: adding 15g of copper acetate and 330ml of tetrahydrofuran solution of 3M magnesium methyl chloride into 1500ml of tetrahydrofuran under the protection of argon, adding 50g of 6, 7-didehydro norethindrone (1) into the tetrahydrofuran solution at the temperature of-30 ℃ under stirring at low temperature for reaction, adding the reaction solution into 1200ml of 20% sulfuric acid aqueous solution after the thin-layer chromatography shows that the raw materials are completely converted, adding 1000ml of n-butyl acetate for extraction, washing an organic layer to be neutral, concentrating, filtering and drying to obtain 43.0g of intermediate (2);
step 2: under the protection of argon, 43.0g of the intermediate (2) is added into 100ml of methanol and 500ml of toluene, 0.9g of pyridine hydrochloride is added, reflux dehydration and stirring reaction are carried out, after thin-layer chromatography shows that the raw materials are completely converted, 1ml of triethylamine is added, the temperature is reduced to-20 ℃, and filtration is carried out, thus obtaining 34.2g of the intermediate (3);
and step 3: adding 34.2g of the intermediate (3) into 500ml of ethanol, adding 200ml of 2% oxalic acid aqueous solution, stirring for reaction at 20 ℃, after thin-layer chromatography analysis shows that the raw materials are completely converted, neutralizing with 5% sodium bicarbonate aqueous solution, adding water for water precipitation, filtering to obtain a crude product, and refining the crude product with butanone once to obtain 30.5g of tibolone. The total mass yield is 61.0 percent, and the product purity is 99.1 percent
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (5)
1. A preparation method of tibolone is characterized in that the synthetic route of the method is as follows:
the method specifically comprises the following steps:
1) and (3) performing a Grignard reaction: under the protection of inert gas, adding a metal catalyst and a methylation reagent into an organic solvent A, adding 6, 7-didehydro norethindrone (1) into the organic solvent A under the low-temperature stirring at the temperature of between 40 ℃ below zero and 20 ℃ below zero for reaction, after the thin-layer chromatography shows that the raw materials are completely converted, adding a reaction solution into an acid solution A, extracting the reaction solution with an organic solvent B, washing an organic layer with water to be neutral, concentrating, filtering and drying to obtain an intermediate (2);
2) double etherification reaction: under the protection of inert gas, adding the intermediate (2) obtained in the step 1) into methanol, adding an acid catalyst and a dehydrating agent, stirring and reacting at 20-50 ℃, adding an organic base after the thin-layer chromatography shows that the raw materials are completely converted, cooling to-20-0 ℃, and filtering to obtain an intermediate (3);
or
Adding the intermediate (2) obtained in the step 1) into an organic solvent C, adding methanol and an acidic catalyst, stirring, refluxing and dehydrating, adding an organic base after the thin-layer chromatography shows that the raw materials are completely converted, cooling to-20-0 ℃, and filtering to obtain an intermediate (3);
3) and (3) hydrolysis reaction: adding the intermediate (3) obtained in the step 2) into an organic solvent D, adding an acid solution B, stirring at 5-25 ℃ for reaction, adding an alkali solution for neutralization after the thin-layer chromatography shows that the raw materials are completely converted, adding water for elutriation, filtering to obtain a crude product, and refining the crude product once by using an organic solvent E to obtain tibolone.
2. The tibolone preparation method according to claim 1, characterized in that in step 1), the organic solvent A is one of tetrahydrofuran, methyltetrahydrofuran or diethyl ether, and the volume dosage is 10-50 times of the weight of the substrate 6, 7-didehydronorethindrone (1); the metal catalyst is one of cuprous chloride, cupric chloride, cuprous bromide, cuprous iodide, cupric acetate or cuprous acetate, and the weight amount of the metal catalyst is 0.05-0.5 times of the weight of the substrate 6, 7-didehydrogenation norethindrone (1); the methylation reagent is one of tetrahydrofuran or diethyl ether solution of methyl magnesium chloride, tetrahydrofuran or diethyl ether solution of methyl magnesium bromide and tetrahydrofuran or diethyl ether solution of methyl magnesium iodide, the molar concentration of the methylation reagent is 1-5 mol/L, and the molar amount of the methylation reagent is 3-10 times of that of the substrate 6, 7-didehydrogenation norethindrone (1); the acid solution A is one of dilute sulfuric acid, dilute hydrochloric acid water solution or acetic acid water solution, the mass concentration of the acid solution A is 5-30%, and the volume consumption of the acid solution A is 15-40 times of the weight of the substrate 6, 7-didehydro norethindrone (1); the organic solvent B is one of dichloromethane, dichloroethane, ethyl acetate, toluene or n-butyl acetate, and the volume consumption of the organic solvent B is 5-30 times of the weight of the substrate 6, 7-didehydro-norethindrone (1).
3. The tibolone preparation method according to claim 1, characterized in that the volume usage of the methanol in step 2) is 1-15 times of the weight of the input intermediate (2); the acid catalyst is one of glacial acetic acid, malonic acid, p-toluenesulfonic acid, benzenesulfonic acid, pyridine hydrobromide or pyridine hydrochloride, and the weight amount of the acid catalyst is 0.01-0.2 times of the weight of the input intermediate (2); the dehydrating agent is one of Dicyclohexylcarbodiimide (DCC), boron trifluoride diethyl etherate, N-Diisopropylcarbodiimide (DIC), N-Carbonyldiimidazole (CDI) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), and the weight amount of the dehydrating agent is 0.5-2 times of the weight of the input intermediate (2); the organic solvent C is one of toluene, xylene, cyclohexane, n-hexane, petroleum ether, octane or heptane, and the volume consumption of the organic solvent C is 5-30 times of the weight of the input intermediate (2); the organic base is pyridine or triethylamine, and the volume usage amount of the organic base is 0.01-0.2 time of the weight of the input intermediate (2).
4. The tibolone preparation method according to claim 1, characterized in that in step 3), the organic solvent D is one of methanol, ethanol, isopropanol, acetone, butanone, tetrahydrofuran or methyltetrahydrofuran, and the volume usage amount is 5-30 times of the weight of the input intermediate (3); the acid solution B is one of oxalic acid, formic acid, acetic acid, malonic acid or propionic acid aqueous solutions, the volume concentration of the acid solution B is 0.5-10%, and the volume dosage of the acid solution B is 5-30 times of the weight of the added intermediate (3); the alkali solution is one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium sulfite, potassium sulfite, sodium hydroxide or potassium hydroxide water solution, and the mass concentration of the alkali solution is 5-15%; the organic solvent E is at least one of acetone, butanone, methanol, ethanol, dichloromethane, isopropanol or dichloroethane.
5. The tibolone production method of claim 1, wherein said inert gas is nitrogen or argon.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114409717A (en) * | 2021-12-17 | 2022-04-29 | 湖南科益新生物医药有限公司 | Tibolone intermediate etherate and preparation method of tibolone |
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| CN110981930A (en) * | 2019-12-31 | 2020-04-10 | 浙江仙居君业药业有限公司 | Synthesis method of tibolone |
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- 2020-07-09 CN CN202010655830.3A patent/CN111944001A/en active Pending
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| CN1863814A (en) * | 2002-01-21 | 2006-11-15 | 阿克佐诺贝尔公司 | Process for the preparation of 7-alpha-methylsteroids |
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| CN114409717A (en) * | 2021-12-17 | 2022-04-29 | 湖南科益新生物医药有限公司 | Tibolone intermediate etherate and preparation method of tibolone |
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