CN108752409A - The method for preparing epiandrosterone as raw material using androstenedione - Google Patents
The method for preparing epiandrosterone as raw material using androstenedione Download PDFInfo
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- CN108752409A CN108752409A CN201810754782.6A CN201810754782A CN108752409A CN 108752409 A CN108752409 A CN 108752409A CN 201810754782 A CN201810754782 A CN 201810754782A CN 108752409 A CN108752409 A CN 108752409A
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- epiandrosterone
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- androstenedione
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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
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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Abstract
The present invention relates to a kind of method preparing epiandrosterone as raw material using androstenedione, androstenedione passes through 3- carbonyl alkene esterification, the protection of 17- carbonyl ketals is reacted, hydrolyze and the four-step reactions such as palladium carbon catalytic reduction reaction, acid hydrolytic reaction have obtained target product epiandrosterone.Compared with existing synthetic method, this method raw material sources are abundant, cheap, synthesis condition is mild, catalyst reduction effect is good, yield is high, production cost is relatively low, are suitble to industrialized production.
Description
Technical field
The present invention relates to medicine intermediate synthesis technical fields, and in particular to one kind preparing table by raw material of androstenedione
The new method of androsterone.
Background technology
Epiandrosterone can not only be used for synthesizing rocuronium, Vecuronium Bromide etc. high-end as a kind of steroid hormone intermediate
Male sex hormone drug, is also used as the additive of beauty product, while having the effects that anticancer, anti-aging, beauty,
It industrially has broad prospects, structural formula is as follows：
The prior synthesizing method of epiandrosterone is to obtain vinegar after esterification, cracking, oxidation, hydrolysis using Chinese yam saponin as raw material
(II) abbreviation diene is denoted as sour gestation diene alcohol ketone, diene is reset through oximate, backman, hydrolyzed again, obtains dehydroepiandros-sterone
(DHEA), DHEA finally obtains epiandrosterone by hydro-reduction, and said synthesis route is as follows：
However the prior synthesizing method there are routes it is long, process is complicated, yield is low the problems such as, and as synthesizing steroid
The yellow ginger of hormone raw material is limited by factors such as regional and seasonalities, and is influenced by overdeveloped in recent years, with it
As the raw material of synthesizing steroid hormone intermediate, the needs of industrialized production far can not be met.
103102379 B of Chinese patent CN disclose one kind using pregnenolone acetate as raw material, by oximate,
The method that backman is reset and hydrolysis prepares epiandrosterone, reaction equation are as follows：
However the increasingly depleted of the raw material yellow ginger due to producing monoene in recent years, lead to the price of pregnenolone acetate
It rises steadily, production cost is relatively higher.In addition, the above method will use toxic reagent POCl3, there are higher safety
Hidden danger is produced, safe production is unfavorable for.
105801649 A of Chinese patent CN disclose one kind using androstenedione as raw material, with titanium dioxide composite catalyzing
The method that agent selective reduction androstenedione obtains epiandrosterone.However due to having 3 and 17 two carbonyls simultaneously in androstenedione structure
Base, selective reduction effect is poor, causes the yield of epiandrosterone relatively not high.
105503985 A of Chinese patent CN disclose one kind using androstenedione as raw material, are protected by esterification, ketal
Total five steps reaction such as reaction, esterlysis reaction, lithium ammonia reduction reaction, boron hydrogen reduction and hydrolysis is protected, table hero has finally been made
Ketone.But have two step reduction reactions in this method reaction process, respectively lithium ammonia reduction reaction and boron hydrogen reduction hydrolysis,
Reaction process is complicated, and product yield is relatively low.The specific synthetic route of this method is as follows：
It is an object of the invention to overcome above-mentioned variety of problems existing for existing epiandrosterone synthetic method, urged using palladium carbon
Change the existing complicated lithium ammonia of reduction reaction substitution and boron hydrogen reduction reaction, not only optimizes synthetic route, reduce complex process
Degree, also improves product yield, reduces production cost, has preferable industrial applications foreground.
Invention content
The purpose of the present invention is to provide a kind of new method preparing epiandrosterone using androstenedione as raw material, this method with
Androstenedione is raw material, by enesterization protection 3- carbonyls, ketal protection 17- carbonyls, basic hydrolysis reduction, acidic hydrolysis four
Step reaction, finally successfully synthesizes epiandrosterone with relatively simple technique, higher yield.This method is as follows：
(a) under protective atmosphere and catalyst existence condition, androstenedione is dissolved, adds acetic anhydride in 20-80 DEG C
5-30h is reacted, separating-purifying obtains product (2)；
(b) product (2) is uniformly mixed with ethylene glycol, deicer, p-methyl benzenesulfonic acid, and 2-10h is reacted at 20-40 DEG C, is used
Triethylamine is quenched rear separating-purifying and obtains product (3)；
(c) alkaline reagent is added after dissolving product (3), is stirred to react 0.5-5h at 0-80 DEG C, adds palladium catalyst
Carbon pressurizes at 20-100 DEG C carries out reduction reaction 6-24h, and separating-purifying obtains product (4)；
(d) product (4) is dissolved and is heated up, add acid reagent, stirred at 40-60 DEG C and reaction is hydrolyzed, point
Product epiandrosterone is obtained from purification
According to said program, androstenedione in step (a), acetic anhydride, catalyst molar ratio be 1：(5-20):
(0.01-1), the one kind of the catalyst in p-methyl benzenesulfonic acid, sulfuric acid, hydrochloric acid, pyridine hydrochloride.
According to said program, the molar ratio of product (2) and ethylene glycol is 1 in step (b)：(1-40), ethylene glycol and water removal
The volume ratio of agent is 1：(1-30), the deicer are one kind in trimethyl orthoformate or triethyl orthoformate.
According to said program, androstenedione, product (3), product (4) institute are dissolved in step (a), step (c), step (d)
The one kind of the solvent used in methanol, ethyl alcohol, acetone, ether, dichloromethane, chloroform.
According to said program, step (c) alkaline reagent is selected from potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, hydrogen-oxygen
Change one kind in potassium, triethylamine, acid reagent described in step (d) is selected from p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid
In one kind.
According to said program, the mass ratio of product (3) and alkaline reagent is 10 in step (c):(1-30), palladium catalyst
The mass ratio of carbon and product (3) is 1:(10-100).
It is forced into 0.5-2MPa progress reduction reactions after catalyst palladium carbon is added according to said program, in step (c).
According to said program, the pH of acid reagent control mixed solution is added in step (d) between 1-4.
Palladium-carbon catalyst used in this application is that metal palladium powder is loaded to manufactured a kind of black powder on activated carbon
End.Select palladium carbon as a kind of important catalyst in epiandrosterone building-up process, in addition to itself being capable of catalytic hydrogenation unsaturation
Hydrocarbon, it is also contemplated that it is high with hydrogenating reduction, selectivity is good, performance is stable, rate of charge is small, can apply mechanically repeatedly, easily when using
In recycling the advantages that, the reduction step of intermediate product can not only be simplified, and product yield can be improved.
Relative to the technology and method of existing synthesis epiandrosterone, the application has the advantages that：
(1) it uses cheap androstenedione for raw material, simplifies and produced compared with the method for 105503985 A of CN
Journey not only so that synthesis technology is simpler controllable, but also drastically reduces cost of material, does not use that cost is higher, uses
The reagents such as larger lithium metal, ammonium hydroxide, the tert-butyl alcohol, isopropanol, potassium borohydride are measured, production cost is significantly reduced, subtracts simultaneously
Pollution is lacked.
(2) it palladium carbon catalytic efficiency higher and is easier to be separated by filtration, recovery method is simple, reusable, into one
Step reduces catalyst use cost and product separating-purifying cost.
(3) epiandrosterone product yield and purity higher, separating-purifying are simpler.
Specific implementation mode
To make those of ordinary skill in the art fully understand technical scheme of the present invention and advantageous effect, below in conjunction with tool
Body embodiment is further described.
The present invention is divided into following four step using androstenedione synthesis epiandrosterone：
Androstenedione, acetic anhydride, catalyst and organic solvent, control is added in the first step in the three-necked flask of nitrogen protection
Temperature processed is 20-80 DEG C, reacts 5-30 hours, then pours the mixture into elutriation in ice water and obtain alkene esterification products 2；
The obtained alkene esterification products 2 of the first step are added in second step in three-necked flask, add ethylene glycol, deicer with
And p-methyl benzenesulfonic acid reacts 2-10 hours at 20-40 DEG C, and triethylamine is added after reaction and is quenched, is poured into after removing solvent
Elutriation in ice water obtains product 3；
Third walks, and in organic solvent by the dissolving of product 3, adds alkaline reagent and stirs anti-0.5-5h at 0-80 DEG C, so
Catalyst palladium carbon is added afterwards and is forced into 0.5-2MPa reaction 6-24h at 20-100 DEG C, catalyst palladium carbon is removed after having reacted
(recycling) and solvent obtain product 4；
4th step in organic solvent by the dissolving of product 4 stirs certain time, after being warming up to 40-60 DEG C again at room temperature
Acid reagent is added, magnetic agitation is hydrolyzed reaction, solvent is removed under reduced pressure after reaction, obtains final product epiandrosterone.
Complete detailed technology path is as follows：
Embodiment 1
The first step, by androstenedione 100g (0.349mol)), acetic anhydride 200mL (2.12mol), dichloromethane 200mL
In the 1000mL three-necked flasks for sequentially adding nitrogen protection, temperature control is 20 DEG C or so, after stirring to material whole dissolved clarification again
4g (0.023mol) p-methyl benzenesulfonic acid, condensing reflux is added.TLC monitoring reactions, stop reaction, reaction solution are fallen after 20 hours
Enter and carry out elutriation in ice water, filter out solid, places it in drying in vacuum drying chamber, obtain product (2) crude product 108g, weight
Volume production rate 108%.
Second step takes 40mL (0.366mol) trimethyl orthoformate, 80mL (1.44mol) ethylene glycol, 8g (0.046mol)
100g (0.305mol) product (2) crude product, TLC monitoring is added after reacting 2h in three-necked flask, at 40 DEG C in p-methyl benzenesulfonic acid
(VPetroleum ether：VEthyl acetate=2：1) it reacts.Fundamental reaction is complete after 6 hours, adds triethylamine and reaction is quenched, decompression is until residual
Remaining mixture is poured into and carries out elutriation in 1L ice water by small part solvent, is dried in vacuo after filtering out solid, and ketal production is obtained
The crude product 102g of object (3), weight yield 102%.
Third walks, and takes ketal product (3) crude product 100g (0.269mol), and the dissolving of 40mL methanol solutions is added, adds hydrogen
Sodium oxide molybdena 10g, stirring 1h disappears substantially to ketal product at 60 DEG C, 10g palladium charcoals is then added, in 60 DEG C, 2MPa reaction under high pressures
It is reacted 24 hours in kettle.Decompression filters recycling palladium carbon after the completion of reaction, and the production after esterlysis and reduction is obtained after removing first alcohol and water
Object (4) crude product 105g, weight yield 105%, it is 99% that HPLC, which measures product purity,.
4th step takes the product (4) after 100g esterlysis and reduction, 40mL methanol solutions is added, add aqueous hydrochloric acid solution
It is 1-4 to adjust its pH, is reacted at room temperature, TLC monitoring reactions.Solvent is removed after product (4) completely disappears, is finally produced
Product epiandrosterone 102g, weight yield 102%, it is 98% that HPLC, which measures product purity,.
Embodiment 2
The first step is same as Example 1.
Second step takes 30mL (0.275mol) trimethyl orthoformate, 100mL (1.80mol) ethylene glycol, 20g to toluene sulphur
Acid reacts 2h in 1L three-necked flasks at 20 DEG C, adds enester crude product made from 80g (0.244mol) previous step, TLC
Monitoring reaction.Fundamental reaction is complete after 9 hours, triethylamine is added, reaction is quenched, solvent is removed under reduced pressure, pours the mixture into ice
Elutriation is carried out in water, is dried in vacuo after filtering out solid, and the crude product 89g of ketal product (3), weight yield 102.5% are obtained.
Subsequent step is same as Example 1.
Embodiment 3
The first step and second step are same as Example 1.
Third walks, and takes ketal crude product 100g (0.269mol) made from previous step, and the dissolving of 40mL methanol solutions is added, then
Sodium tert-butoxide 10g is added, stirring 1h is completely disappeared to product (2) at 80 DEG C, 10g palladium charcoals is then added, in 80 DEG C, 2MPa high
It is reacted 24 hours in pressure reaction kettle.Decompression filters after the completion of reaction, recycles palladium carbon, removes first alcohol and water, obtains esterlysis and reduction
Product (4) 103g afterwards, weight yield 103%, it is 96% that HPLC, which measures product purity,.
4th step is same as Example 1.
Embodiment 4
The first to three step is same as Example 1.
4th step takes the product (4) after 100g esterlysis and reduction, 40mL methanol solutions is added, add 2g to toluene sulphur
Acid reacts at 80 DEG C, TLC monitoring reactions.It waits for that reaction is completely disappeared to product 4, obtains final products epiandrosterone 103g, weight
Yield 103%, it is 97% that HPLC, which measures product purity,.
Claims (10)
1. a kind of method preparing epiandrosterone as raw material using androstenedione, it is characterised in that include the following steps：
(a) under protective atmosphere and catalyst existence condition, androstenedione is dissolved, adds acetic anhydride in 20-80 DEG C of reaction
5-30h, separating-purifying obtain product (2)；
(b) product (2) is uniformly mixed with ethylene glycol, deicer, p-methyl benzenesulfonic acid, reacts 2-10h at 20-40 DEG C, with three second
Amine is quenched rear separating-purifying and obtains product (3)；
(c) alkaline reagent is added after dissolving product (3), is stirred to react 0.5-5h at 0-80 DEG C, adds catalyst palladium carbon and exist
Compressive reaction 6-24h at 20-100 DEG C, separating-purifying obtain product (4)；
(d) product (4) is dissolved and is heated up, add acid reagent, stirred at 40-60 DEG C and reaction is hydrolyzed, separation carries
It is pure to obtain product epiandrosterone
2. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：Androstenedione in step (a), acetic anhydride,
The molar ratio of catalyst is 1:(5-20):(0.01-1).
3. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：Product (2) and ethylene glycol in step (b)
Molar ratio is 1：The volume ratio of (1-40), ethylene glycol and deicer is 1：(1-30).
4. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：The catalyst be selected from p-methyl benzenesulfonic acid,
One kind in sulfuric acid, hydrochloric acid, pyridine hydrochloride, the deicer are one kind in trimethyl orthoformate or triethyl orthoformate.
5. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：In step (a), step (c), step (d)
Dissolve androstenedione, product (3), solvent used in product (4) is selected from methanol, ethyl alcohol, acetone, ether, dichloromethane, chloroform
In one kind.
6. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：Alkaline reagent described in step (c) is selected from
One kind in potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, triethylamine.
7. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：Acid reagent described in step (d) is selected from
One kind in p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid.
8. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：Product (3) and alkaline reagent in step (c)
Mass ratio be 10:The mass ratio of (1-30), catalyst palladium carbon and product (3) is 1:(10-100).
9. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：After catalyst palladium carbon is added in step (c)
It is forced into 0.5-2MPa and carries out reduction reaction.
10. the method as described in claim 1 for preparing epiandrosterone, it is characterised in that：Acid reagent control is added in step (d)
The pH of mixed solution is between 1-4.
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| CN201810754782.6A CN108752409B (en) | 2018-07-10 | 2018-07-10 | Method for preparing epiandrosterone by using androstenedione as raw material |
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| CN201810754782.6A CN108752409B (en) | 2018-07-10 | 2018-07-10 | Method for preparing epiandrosterone by using androstenedione as raw material |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233806A (en) * | 2020-03-20 | 2020-06-05 | 武汉轻工大学 | Preparation method of 3,5, 4' -triacetoxy-7-hydroxyflavone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101845073A (en) * | 2010-06-23 | 2010-09-29 | 瑞阳制药有限公司 | Preparation method and application of 1alpha-dehydroepiandrosterone |
| CN105503985A (en) * | 2016-02-23 | 2016-04-20 | 浙江仙琚制药股份有限公司 | Method for preparing epiandrosterone |
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2018
- 2018-07-10 CN CN201810754782.6A patent/CN108752409B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101845073A (en) * | 2010-06-23 | 2010-09-29 | 瑞阳制药有限公司 | Preparation method and application of 1alpha-dehydroepiandrosterone |
| CN105503985A (en) * | 2016-02-23 | 2016-04-20 | 浙江仙琚制药股份有限公司 | Method for preparing epiandrosterone |
Non-Patent Citations (1)
| Title |
|---|
| BARBORA SLAVÍKOVÁET AL.: "《Allopregnanolone and Pregnanolone Analogues Modified in the C Ring: Synthesis and Activity》", 《J. MED. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233806A (en) * | 2020-03-20 | 2020-06-05 | 武汉轻工大学 | Preparation method of 3,5, 4' -triacetoxy-7-hydroxyflavone |
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