CN114478672A - Synthetic method of HE3286 - Google Patents

Synthetic method of HE3286 Download PDF

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CN114478672A
CN114478672A CN202210119479.5A CN202210119479A CN114478672A CN 114478672 A CN114478672 A CN 114478672A CN 202210119479 A CN202210119479 A CN 202210119479A CN 114478672 A CN114478672 A CN 114478672A
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solvent
compound
reaction
weight ratio
acid
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CN114478672B (en
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张峥斌
李纯
尹金玉
张杰锋
吴静
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Jiangxi Junye Biological Pharmaceutical Co ltd
Zhejiang Xianju Junye Pharmaceutical Co ltd
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Jiangxi Junye Biological Pharmaceutical Co ltd
Zhejiang Xianju Junye Pharmaceutical Co ltd
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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
    • C07J1/0003—Androstane derivatives
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
    • C07J1/004—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0048—Alkynyl derivatives

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Abstract

A synthetic method of HE3286 is characterized in that trihydroxy substances (I) are used as raw materials, HE3286 is obtained through the following steps of transposition reaction, double esterification reaction, elimination reaction, hydrogenation reaction, alkynylation reaction and hydrolysis reaction, and the HE3286 is obtained.

Description

Synthetic method of HE3286
Technical Field
The invention relates to a preparation method of an androstane compound.
Background
HE3286, chemically named 17 alpha-ethynylandrost-5-ene-3 beta, 7 beta, 17 beta-triol, is used for preventing or treating metabolic diseases such as type 2 diabetes, hyperglycemia and the like and autoimmune diseases such as rheumatoid arthritis and the like.
So far, WO2009149392 reports 3 synthetic routes to HE 3286.
In the first synthetic route, DHEA is used as an initial raw material, 3-position hydroxyl is protected by TMSCl, then 2 is obtained by adding acetylene to 17-position keto, 7-position keto compound 4 is obtained by oxidation after 3-position acetyl protection, 7-position beta hydroxyl 5 is obtained by reducing compound 4, and finally 3-position hydrolysis is carried out to obtain a target product HE 3286. After 6 steps of reaction, the target product HE3286 is obtained with the total yield of 15%.
Figure BSA0000265344390000011
In the second synthetic route, rearrangement (DHEA acetate) is used as a starting material, a compound 6 is obtained through ethylene glycol protection, a compound 7 is obtained through 7-site oxidation, a compound 8 is obtained through reduction, then ethylene glycol protection, 3-site ester hydrolysis and 3, 7-site hydroxyl TMS protection are carried out, a compound 11 is obtained, 17-site alkynyl is carried out, and finally TMS deprotection is carried out to obtain a target product HE 3286. After 8 steps of reaction, the target product HE3286 is obtained with the total yield of 6%.
Figure BSA0000265344390000012
Figure BSA0000265344390000021
The third synthesis route still uses rearrangement (DHEA acetate) as the starting material, and the compound 13 is obtained by oxidation, the compound 14 is obtained by hydroxylamine amination at the 17-position, and then the 7-position is reduced and the 17-position is hydrolyzed to obtain the intermediate 9, and the intermediate 9 is used for reaching the target product HE3286, which is consistent with the second synthesis route. After 8 steps of reaction, the target product HE3286 is obtained with the total yield of 30%.
Figure BSA0000265344390000022
Compared with the first and the second synthetic routes, although the yield of the third synthetic route is improved to 30% from the previous 15%, the problems of long route, complex operation and the like still exist
Based on the problems in the prior art, a new synthesis method of HE3286 is provided by combining the existing steroid intermediate product line of the applicant, so that the reaction steps are shortened, and the total reaction yield is further improved, which is a problem to be solved in the prior art.
Disclosure of Invention
In order to solve the problems in the prior art, a novel synthesis method of HE3286 is provided. The method takes drospirenone intermediate trihydroxy compound (I) (CAS: 2963-69-1; 3 beta, 7 alpha, 15 alpha-trihydroxyandrost-5-ene-17-one) in the existing product line of the applicant as a starting material, and reduces the past 8 steps of reaction to 6 steps through transposition, double esterification, elimination, hydrogenation, alkynization and hydrolysis, thereby greatly improving the reaction yield by 80 percent compared with the past reported synthetic route. Since the cost of the trihydroxy compound (I) is lower than that of DHEA and DHEA acetate, the process cost of the invention is greatly reduced compared with the reported process.
The technical scheme provided by the invention is as follows:
a process for synthesizing HE3286 from trihydroxy substance (I) includes transposition reaction, double esterification, elimination reaction, hydrogenation reaction, acetylization reaction and hydrolysis reaction
Figure BSA0000265344390000031
The synthesis method specifically comprises the following steps:
1) transposition reaction
Dissolving trihydroxy substance (I) in solvent, adding strong acid, heating at room temperature for reflux reaction, adding alkali for neutralization after reaction, extracting with organic solvent, washing the organic phase with saturated salt water, layering, drying, and concentrating to obtain compound (II).
As a preferred technical scheme, the solvent is selected from acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, dioxane, DMF, DMSO, methanol, ethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether, preferably acetone; the volume weight ratio of the acetone to the trihydroxy substances is preferably 6-15: 1; the strong acid is selected from perchloric acid, hydrochloric acid, sulfuric acid or nitric acid, and the weight ratio of the strong acid to the trihydroxy substance (I) is 0.01-1; the strong acid is preferably perchloric acid; the weight ratio of perchloric acid to trihydroxy compounds is 0.04-0.06: 1, and the reaction temperature is 15-40 ℃. The extraction solvent is preferably ethyl acetate.
2) Double esterification reaction
Dissolving the compound (II) in an organic solvent, adding an acid-binding agent, adding pivaloyl chloride at the temperature of 0-50 ℃, reacting, adding an alkali solution for neutralization, washing an organic phase with water and saturated salt water respectively, layering, drying and concentrating the organic phase to obtain a compound (III).
As a preferred technical scheme, the solvent is dichloromethane or chloroform, preferably dichloromethane; the acid-binding agent is selected from pyridine, triethylamine, 4-Dimethylaminopyridine (DMAP) and Diisopropylethylamine (DIPEA), and the weight ratio of the acid-binding agent to the compound (II) is 0.1-10; the acid binding agent is preferably pyridine, the molar ratio of the pivaloyl chloride to the compound (II) is preferably 2.5-3.5: 1, and the molar ratio of the pyridine to the pivaloyl chloride is 1.2-1.5: 1; the reaction temperature is 15-40 ℃.
3) Hogwash removal reaction
Dissolving the compound (III) in a solvent, reacting with alkali at the temperature of 20-70 ℃, quenching, extracting a water layer, combining organic phases, washing with saturated salt water, layering, drying, concentrating the organic phase to obtain a crude compound (IV), adding a pulping solvent for pulping, and filtering to obtain the refined compound (IV).
As a preferred technical scheme, the solvent is selected from one or more of tetrahydrofuran, dioxane, DMF, DMSO, methanol, ethanol, diethyl ether, isopropyl ether, and methyl tert-butyl ether, preferably one of tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, and methyl tert-butyl ether, and more preferably tetrahydrofuran; the alkali is selected from potassium acetate, sodium carbonate, sodium hydroxide or potassium hydroxide, the weight ratio of the alkali to the compound (III) is 0.1-10, preferably 0.2-0.8, the alkali is preferably potassium acetate, the weight ratio of the potassium acetate to the compound (III) is preferably 0.4-0.6, the reaction temperature is 55-65 ℃, a saturated ammonium chloride solution is adopted for quenching, and ethyl acetate is used as an extraction solvent; the pulping solvent is a mixed solvent of petroleum ether and ethyl acetate, the ratio is 1-20: 1, preferably 14-18: 1, and the volume-weight ratio of the pulping solvent to the compound (III) is 2.5-3.5: 1.
4) Hydrogenation reaction
Dissolving the compound (IV) in a solvent, adding a palladium-carbon catalyst (Pd/C) at 0-50 ℃ for hydrogenation reduction, filtering after the reaction is finished, washing a filter cake by the solvent, and concentrating to obtain a compound (V).
Preferably, the solvent for the hydrogenation reduction reaction is one or a mixture of two solvents such as methanol, ethanol, ethyl acetate, tetrahydrofuran, and the like, more preferably methanol, and the solvent for washing is ethyl acetate. The weight ratio of the palladium-carbon catalyst to the compound (IV) is 0.03-0.07, and H2The pressure is maintained at 10-20 Psi, the reaction temperature is preferably 15-30 ℃, and the volume-to-weight ratio of the methanol to the compound (IV) is 8-11: 1.
5) Alkynylation reaction
Dissolving the compound (V) in an organic solvent, adding an ethynyl Grignard reagent under the protection of nitrogen, and reacting at-10 ℃ to complete under reflux. Adding ammonium salt solution to quench reaction, adding water to separate layers, extracting water layer with organic solvent, mixing organic phases, separating layers, washing with water, separating layers again, washing with saturated salt solution, separating layers, drying, concentrating organic phase, adding pulping solvent into product, pulping, filtering, and drying to obtain compound (VI).
As a preferred technical scheme, the solvent is selected from tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether and ethylene glycol dimethyl ether, and is preferably tetrahydrofuran. The ethynyl grignard reagent is preferably ethynyl magnesium bromide, and the molar ratio of the ethynyl magnesium bromide to the compound (V) is 1.05 to 5, more preferably 1.05 to 1.2; the temperature of the reaction system is controlled to be-10-0 ℃ when the acetenyl magnesium bromide is dripped, and the reaction temperature is controlled to be 30-40 ℃ after dripping. The ammonium salt solution is an ammonium chloride aqueous solution, the extracted organic solvent is preferably ethyl acetate, the beating solvent is acetonitrile, and the volume-weight ratio of the beating solvent to the compound V is 1-2.
6) Hydrolysis reaction
Dissolving the compound (VI) in a solvent, adding alkali, heating at room temperature to reflux and react completely, adding the reaction solution into water at room temperature, separating out solids, filtering to obtain a target product HE3286 crude product, and recrystallizing to obtain the target product HE 3286.
As a preferred technical solution, the solvent is selected from methanol, ethanol or tetrahydrofuran, preferably methanol; the volume-weight ratio of the methanol to the compound (VI) is 8-12: 1; the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate, and the weight ratio of the alkali to the compound (VI) is 0.1-10, more preferably 0.2-1; the alkali is preferably potassium hydroxide, the weight ratio of the potassium hydroxide to the compound (VI) is 2.5-3: 1, and the reaction temperature is preferably 45-55 ℃.
The recrystallization solvent is methanol with the water content of 7-10% by volume percentage. The recrystallization method comprises the steps of completely dissolving the HE3286 crude product in a recrystallization solvent, evaporating partial methanol until solid begins to be separated out, cooling to-10-5 ℃ for crystallization, filtering and drying to obtain the target product HE 3286.
The HE3286 synthesis method provided by the invention selects different raw materials and synthesis routes, takes an important intermediate compound (I) produced by drospirenone as an initial raw material, and obtains the target product HE3286 through transposition, double esterification, elimination, hydrogenation, alkynylation and hydrolysis, thereby greatly improving the total yield of the reaction to about 80% on the basis of the prior art. The trihydroxy compound (I) is an intermediate compound which is efficiently converted from DHEA by the applicant in a biological fermentation method and is produced on a large scale. By adopting the synthesis method provided by the invention, the HE3286 is produced by taking the trihydroxy substances as the raw materials through reasonably designing a route and selecting proper reaction conditions, so that the yield of the HE3286 can be greatly improved, the production cost is reduced, and the production efficiency is improved.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1
Triolate (I) (1.0kg, HPLC content 99.1%) was dissolved in acetone (10L), and perchloric acid (50g) was added to the solution to react at room temperature for 2 hours. TLC detection reaction was complete, saturated sodium bicarbonate was neutralized, water (2L) was added, ethyl acetate (5L) was extracted, the layers were separated, saturated brine was washed (2L), the layers were separated, dried over anhydrous sodium sulfate, and concentrated to give compound (II) (991.0g) as a pale yellow solid with a molar yield of 99.1%.
Example 2
Dissolving compound (II) (750.0g) in dichloromethane (7.5L), adding pyridine (370.0g), stirring at room temperature, adding pivaloyl chloride (423.3g) in portions, stirring at room temperature, reacting, adding saturated sodium bicarbonate solution to neutralize, separating layers, washing dichloromethane layer with water (1.5L), separating layers, washing with saturated saline (1.5L), separating layers, drying with anhydrous sodium sulfate, concentrating to obtain compound (V) (1.14kg) with molar yield of 99.5%
Example 3
Compound (III) (500.0g) was dissolved in THF (2500mL), and potassium acetate (251g) was added thereto, followed by heating and refluxing for 16 hours. The reaction was completed by TLC detection and stopped. Cooling to normal temperature, adding saturated NH4Cl solution (500mL), layers were separated, the aqueous layer was extracted with ethyl acetate (300mL), layers were separated, the organic layers were combined, washed with saturated brine (500mL), layers were separated, concentrated, and dried to give crude compound (IV) as a pale yellow solid (480.0 g). Petroleum Ether (PE)/Ethyl Acetate (EA) ═ 15/1(1600mL, v/v) was slurried to give compound (IV) (381.0g) as a white solid in 96.4 mole yield.
Example 4
Compound (IV) (230g) was dissolved in methanol (2300mL), and 5% Pd/C (11.5g), H was added2(15Psi), reaction at 25 ℃ for 2 hours, TLC check of reaction completion, suction filtration, cake washing with Ethyl Acetate (EA) twice, 300mL each, drying to give compound (V) (229.0g) as a white solid in 99% molar yield.
Example 5
Compound (V) (180.0g) was dissolved in a THF (1L) solution, and ethynylmagnesium bromide (1.95L, 0.5M in THF) was added dropwise at 0 ℃ and stirred at room temperature for 1 hour. The temperature is raised to 35 ℃ for reaction for 3 hours. The reaction was completed by TLC detection and stopped. Cooling to normal temperature, and dropwise adding saturated NH4The reaction was quenched with Cl solution (200mL), water (500mL) was added, the layers were separated, the aqueous layer was extracted with ethyl acetate (500mL), the layers were separated, the organic layers were combined, washed with saturated brine (500mL), the layers were separated, dried, and concentrated to give crude compound (VI) as a pale yellow solid (190.0 g). Slurried with (300mL) acetonitrile, filtered and dried to give compound (VI) (175.0g) as a white solid in 91% molar yield.
Example 6
Compound 19(150.0g) was dissolved in a methanol (1.5L) solution, KOH (40.5g) was added, and the mixture was heated to 50 ℃ and stirred for 16 hours. The reaction was completed by TLC detection and stopped. And (3) cooling to normal temperature, dropwise adding the reaction solution into (7.5L) water, carrying out suction filtration, and drying to obtain a compound HE3286(115.0g) as a beige solid. Recrystallization, adding 115 g of compound 4 into methanol/water (10/1 (v/v, 2000mL), heating and refluxing until the mixture is completely dissolved, evaporating partial methanol until solid is precipitated, cooling to 0 ℃ for crystallization, performing suction filtration, and drying to obtain the target compound HE3286(110.2g, HPLC content 99.2%) as a white solid, wherein the molar yield is 92%.

Claims (12)

1. A process for synthesizing HE3286 from trihydroxy substance (I) includes transposition reaction, double esterification, elimination reaction, hydrogenation reaction, acetylization reaction and hydrolysis reaction
Figure FSA0000265344380000011
The synthesis method specifically comprises the following steps:
1) transposition reaction
Dissolving trihydroxy substance (I) in solvent, adding strong acid, heating at room temperature for reflux reaction, adding alkali for neutralization after reaction, extracting with organic solvent, washing the organic phase with saturated salt water, layering, drying, and concentrating to obtain compound (II);
2) double esterification reaction
Dissolving the compound (II) in an organic solvent, adding an acid-binding agent, adding pivaloyl chloride at the temperature of 0-50 ℃, reacting, adding an alkali solution for neutralization, washing an organic phase with water and saturated salt water respectively, layering, drying and concentrating the organic phase to obtain a compound (III);
3) elimination reaction
Dissolving the compound (III) in a solvent, reacting with alkali at the temperature of 20-70 ℃, quenching, extracting a water layer, combining organic phases, washing with saturated salt water, layering, drying, concentrating the organic phase to obtain a crude compound (IV), adding a pulping solvent for pulping, and filtering to obtain a refined compound (IV);
4) hydrogenation reaction
Dissolving the compound (IV) in a solvent, adding a palladium-carbon catalyst (Pd/C) at 0-50 ℃ for hydrogenation reduction, filtering after the reaction is finished, washing a filter cake by the solvent, and concentrating to obtain a compound (V).
5) Alkynylation reaction
Dissolving the compound (V) in an organic solvent, adding an ethynyl Grignard reagent under the protection of nitrogen, and reacting at-10 ℃ to complete under reflux. Adding ammonium salt solution to quench reaction, adding water to separate layers, extracting water layer with organic solvent, mixing organic phases, separating layers, washing with water, separating layers again, washing with saturated salt solution, separating layers, drying, concentrating organic phase, adding pulping solvent into product, pulping, filtering, and drying to obtain compound (VI);
6) hydrolysis reaction
Dissolving the compound (VI) in a solvent, adding alkali, heating at room temperature to reflux and react completely, adding the reaction solution into water at room temperature, separating out solids, filtering to obtain a target product HE3286 crude product, and recrystallizing to obtain the target product HE 3286.
2. The method for synthesizing HE3286 according to claim 1, wherein in step 1), the solvent is selected from acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, dioxane, DMF, DMSO, methanol, ethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether; (ii) a The strong acid is selected from perchloric acid, hydrochloric acid, sulfuric acid or nitric acid, and the weight ratio of the strong acid to the trihydroxy substance (I) is 0.01-1.
3. The synthesis method of HE3286, according to claim 2, wherein in step 1), the solvent is preferably acetone, and the volume weight ratio of acetone to the trihydroxy compound is preferably 6-15: 1; the strong acid is preferably perchloric acid; the weight ratio of perchloric acid to trihydroxy compounds is 0.04-0.06: 1, and the reaction temperature is 15-40 ℃. The extraction solvent is preferably ethyl acetate.
4. A method of synthesizing HE3286 according to claim 1, wherein in step 2), the solvent is dichloromethane or chloroform; the acid-binding agent is selected from pyridine, triethylamine, 4-Dimethylaminopyridine (DMAP) and Diisopropylethylamine (DIPEA), and the weight ratio of the acid-binding agent to the compound (II) is 0.1-10.
5. The synthesis method of HE3286, according to claim 4, wherein in the step 2), the solvent is preferably dichloromethane, the acid-binding agent is preferably pyridine, the molar ratio of pivaloyl chloride to the compound (II) is preferably 2.5-3.5: 1, the molar ratio of pyridine to pivaloyl chloride is 1.2-1.5: 1, and the reaction temperature is 15-40 ℃.
6. The method for synthesizing HE3286 according to claim 1, wherein in step 3), the solvent is one or more selected from tetrahydrofuran, dioxane, DMF, DMSO, methanol, ethanol, diethyl ether, isopropyl ether and methyl tert-butyl ether; the alkali is selected from potassium acetate, sodium carbonate, sodium hydroxide or potassium hydroxide, the weight ratio of the alkali to the compound (III) is 0.1-10, the pulping solvent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 1-20: 1, the reaction temperature is 55-65 ℃, saturated ammonium chloride solution is adopted for quenching, and ethyl acetate is taken as an extraction solvent.
7. The synthesis method of HE3286, according to claim 1, wherein in step 3), the solvent is preferably one of tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl tert-butyl ether, the base is preferably potassium acetate, and the weight ratio of potassium acetate to compound (III) is preferably 0.4-0.6; the pulping solvent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 14-18: 1, and the volume weight ratio of the pulping solvent to the compound (III) is 2.5-3.5: 1.
8. The synthesis method of HE3286 according to claim 6, wherein in step 4), the solvent for the hydrogenation reduction reaction is one or two of methanol, ethanol, ethyl acetate, tetrahydrofuran, etcMixing the agents, wherein the solvent for cleaning is ethyl acetate. The weight ratio of the palladium-carbon catalyst to the compound (IV) is 0.03-0.07, and H2The pressure is maintained at 10-20 Psi, the reaction temperature is preferably 15-30 ℃, and the volume-to-weight ratio of the methanol to the compound (IV) is 8-11: 1.
9. The method for synthesizing HE3286 according to claim 1, wherein in step 5), the solvent is selected from tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether and ethylene glycol dimethyl ether, the ethynyl grignard reagent is preferably ethynyl magnesium bromide, and the molar ratio of the ethynyl magnesium bromide to the compound (V) is 1.05-5; the temperature of the reaction system is controlled to be-10-0 ℃ when the acetenyl magnesium bromide is dripped, and the reaction temperature is controlled to be 30-40 ℃ after dripping.
10. The method for synthesizing HE3286 according to claim 9, wherein the solvent in step 5) is tetrahydrofuran, the molar ratio of the ethynyl magnesium bromide to the compound (V) is 1.05 to 1.2, the ammonium salt solution is an aqueous ammonium chloride solution, the extracted organic solvent is ethyl acetate, the beating solvent is acetonitrile, and the volume/weight ratio of the beating solvent to the compound V is 1 to 2.
11. The synthesis method of HE3286 according to claim 1, wherein in step 6), the solvent is selected from methanol, ethanol or tetrahydrofuran, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate, the weight ratio of the base to the compound (VI) is 0.1-10, the reaction temperature is preferably 45-55 ℃, the recrystallization solvent is methanol with a water content of 7-10% by volume, the recrystallization method is that the crude HE3286 product is completely dissolved in the recrystallization solvent, part of the methanol is evaporated to precipitate solids, and the target product HE3286 is obtained by cooling, crystallization, filtration and drying.
12. A synthesis process for HE3286 according to claim 11, wherein in step 6), the solvent is preferably methanol; the volume-weight ratio of the methanol to the compound (VI) is 8-12: 1; the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate, and the weight ratio of the alkali to the compound (VI) is 0.1-10, more preferably 0.2-1; the alkali is preferably potassium hydroxide, and the weight ratio of the potassium hydroxide to the compound (VI) is 2.5-3: 1.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435327A (en) * 1981-09-21 1984-03-06 Schering, Aktiengesellschaft 3β,7β,15α-Trihydroxy-5-androsten-17-one, its 3,15-dipivalate, and their preparation
CN1694897A (en) * 2002-11-06 2005-11-09 法玛西亚普强责任有限公司 Processes for preparing 7-carboxy substituted steroids
CN1694894A (en) * 2001-11-14 2005-11-09 森托科尔公司 Anti-IL-6 antibodies, compositions, methods and uses
WO2009149392A1 (en) * 2008-06-06 2009-12-10 Hollis-Eden Pharmaceuticals, Inc. Methods for preparing 17-alkynyl-7-hydroxy steroids and related compounds
CN105246486A (en) * 2013-03-13 2016-01-13 萨奇治疗股份有限公司 Neuroactive steroids and methods of use thereof
CN111410678A (en) * 2019-01-08 2020-07-14 成都康弘药业集团股份有限公司 Steroid compound, use and preparation method thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435327A (en) * 1981-09-21 1984-03-06 Schering, Aktiengesellschaft 3β,7β,15α-Trihydroxy-5-androsten-17-one, its 3,15-dipivalate, and their preparation
CN1694894A (en) * 2001-11-14 2005-11-09 森托科尔公司 Anti-IL-6 antibodies, compositions, methods and uses
CN1694897A (en) * 2002-11-06 2005-11-09 法玛西亚普强责任有限公司 Processes for preparing 7-carboxy substituted steroids
WO2009149392A1 (en) * 2008-06-06 2009-12-10 Hollis-Eden Pharmaceuticals, Inc. Methods for preparing 17-alkynyl-7-hydroxy steroids and related compounds
CN105246486A (en) * 2013-03-13 2016-01-13 萨奇治疗股份有限公司 Neuroactive steroids and methods of use thereof
CN112375115A (en) * 2013-03-13 2021-02-19 萨奇治疗股份有限公司 Neuroactive steroids and methods of use thereof
CN111410678A (en) * 2019-01-08 2020-07-14 成都康弘药业集团股份有限公司 Steroid compound, use and preparation method thereof

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