CN105801648A - Technology for refining 4-androstenedione from dehydroepiandrosterone mother solution - Google Patents
Technology for refining 4-androstenedione from dehydroepiandrosterone mother solution Download PDFInfo
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- CN105801648A CN105801648A CN201610244536.7A CN201610244536A CN105801648A CN 105801648 A CN105801648 A CN 105801648A CN 201610244536 A CN201610244536 A CN 201610244536A CN 105801648 A CN105801648 A CN 105801648A
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- dehydroepiandros
- mother solution
- sterone
- refining
- organic solvent
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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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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a technology for refining 4-androstenedione from a dehydroepiandrosterone mother solution. The technology comprises the steps that dehydroepiandrosterone is pretreated, reflux dehydration, addition of a weak oxidant, reflux dehydration and addition of aluminum isopropoxide for a reaction are carried out in sequence, an alkaline aqueous solution is added for a reaction, washing and distillation are carried out, and crude 4-androstenedione is obtained; then refining and purifying are carried out, and the 4-androstenedione product high in purity and yield is obtained.
Description
Technical field
The present invention relates to the processing method of dehydroepiandros-sterone mother solution, be specifically related to a kind of from dehydroepiandros-sterone mother solution
The technique refining 4-AD.
Background technology
Dehydroepiandros-sterone, chemical name: 3 beta-hydroxy-5-androstene-17-ketone, i.e. DHEA, molecular formula is C19H28O2。
Dehydroepiandros-sterone is for manufacturing the important intermediate of steroid hormone class medicine and raw material, have simultaneously defying age and
Protein assimilation.
The manufacturer of domestic dehydroepiandros-sterone, utilized diosgenin or Dioscorea nipponica Mak. Ningpo Yam Rhizome Saponin, in the past through open loop
Acylated oxydrolysis oximate Beckmann rearrangement hydrolysis, hydrolysis, obtain dehydroepiandros-sterone, this work
Skill route is long, and raw material Saponin region is strong, resource-constrained, and production cost is high, and complex operation, environmental pollution is big.
In recent years, increasing scholar utilizes plant sterol tunning 4-AD, i.e. 4-AD to be former
Material synthesizes dehydroepiandros-sterone, and the DHEA crude product of synthesis carries out solvent refining, can obtain DHEA qualified
Product and DHEA mother solution, containing dehydroepiandros-sterone in DHEA mother solution, 3 Alpha-hydroxy-5-androstene-17-ketone and 3,17-
The key components such as double Betamethasone Ketal structures.The method refining 4-AD from DHEA mother solution is by prior art,
First by DHEA mother solution by column chromatography for separation, separating obtained material is synthesized 4-AD, above refinement
The 4-AD recovery rate that method obtains is low.
Summary of the invention
For defect present in prior art, it is an object of the invention to provide a kind of waste and old utilization, green ring
Guarantor, the technique refining 4-AD from dehydroepiandros-sterone mother solution that recovery rate is high.
For reaching object above, the present invention adopts the technical scheme that: a kind of refinement from dehydroepiandros-sterone mother solution
The technique of 4-AD, comprises the following steps:
S1, takes the dehydroepiandros-sterone mother solution to obtain during 4-AD synthesis dehydroepiandros-sterone, adds
Non-polar organic solvent, at 50～55 DEG C after heating for dissolving, with the acid solution molten clear pH value of regulation to 2～3, separates
Lower layer of water, hot water wash upper liquid to pH is 6～7；
S2, upper liquid step S1 obtained is heated to 110～112 DEG C, reflux dewatering, then is cooled to
80～90 DEG C, adding weak oxidant, reflux dewatering to effluent is clarified；
S3, after dehydration, is cooled to 100～110 DEG C, adds aluminum isopropylate., is to slowly warm up to 110～114 DEG C,
Reaction 5～8h, sampling is done TLC point plate and is detected until reacting complete；
S4, after completion of the reaction, is cooled to 80～90 DEG C, adds alkaline aqueous solution, after reaction 1～2h, while hot
Separating and remove alkaline aqueous solution, use hot water wash reactant liquor, punching evaporates, and obtains 4-AD crude product；
S5, the molten clear middle addition polar organic solvent that step S4 is obtained and basic salt, it is heated to reflux 1.5～3.5
Hour, adding activated carbon, sucking filtration, concentrating under reduced pressure goes out polar organic solvent, cooling, and centrifugation is washed
To 4-AD fine work.
On the basis of technique scheme, it is preferred that dehydrogenation in dehydroepiandros-sterone mother solution in described step S1
Epiandrosterone isomer weight/mass percentage composition is 30%～40%.
On the basis of technique scheme, it is preferred that in described step S1, non-polar organic solvent uses first
Benzene, ethyl acetate or chloroform.
On the basis of technique scheme, it is preferred that in described step S1, acid solution is hydrochloric acid, methanol and water
Mixed solution, wherein, every 100kg dehydroepiandros-sterone mother solution correspondence add 20～50kg methanol, 180～480kg
Water and the mixed solution of 20～50kg hydrochloric acid.
On the basis of technique scheme, it is preferred that in described step S2 weak oxidant use Ketohexamethylene or
Calcium hypochlorite.
On the basis of technique scheme, it is preferred that after in described step S4, punching evaporates, emptying water,
Add methanol and activated carbon, reflux decolour at 60～65 DEG C.
On the basis of technique scheme, it is preferred that in described step S5, polar organic solvent uses methanol
Or ethanol.
On the basis of technique scheme, it is preferred that described step S5 neutral and alkali salt uses potassium carbonate or carbon
Acid is received.
On the basis of technique scheme, it is preferred that in described step S5, the molten clear correspondence of each volume adds
Entering the polar organic solvent of 5～15 volumes, concentrating under reduced pressure goes out the polar organic solvent of 4～14 volumes.
On the basis of technique scheme, it is preferred that also include step S6, use by 1.5～3.5 times of matter
The 4-AD fine work that the methanol soaking step S5 of amount obtains, until 4-AD weight/mass percentage composition is big
In 98.5%.
Compared with prior art, it is an advantage of the current invention that:
(1) refining technique of the present invention, gained 4-AD recovery rate is high, and product purity is high；
(2) refining technique of the present invention can reduce the discharge of solid waste, waste and old utilization, be conducive to environmental protection.
Accompanying drawing explanation
Fig. 1 is the FB(flow block) of the technique refining 4-AD from dehydroepiandros-sterone mother solution of the present invention.
Detailed description of the invention
Shown in Figure 1, what the embodiment of the present invention provided refines 4-AD from dehydroepiandros-sterone mother solution
Technique, it is necessary first to mother solution pretreatment: S1, take with 4-AD synthesis dehydroepiandros-sterone during
The dehydroepiandros-sterone mother solution obtained, adds non-polar organic solvent, at 50～55 DEG C after heating for dissolving, uses acid solution
Regulating molten clear pH value to 2～3, separate lower layer of water, hot water wash upper liquid to pH is 6～7.
Next to that the process of chemical reactive synthesis 4-AD, including:
S2, upper liquid step S1 obtained is heated to 110～112 DEG C, reflux dewatering, then is cooled to
80～90 DEG C, adding weak oxidant, reflux dewatering to effluent is clarified；
S3, after dehydration, is cooled to 100～110 DEG C, adds aluminum isopropylate., is to slowly warm up to 110～114 DEG C,
Reaction 5～8h, sampling is done TLC point plate and is detected until reacting complete.
Then, isolated 4-AD crude product, including:
S4, after completion of the reaction, is cooled to 80～90 DEG C, adds alkaline aqueous solution, after reaction 1～2h, while hot
Separating and remove alkaline aqueous solution, use hot water wash reactant liquor, punching evaporates, and obtains 4-AD crude product.
Subsequently, to 4-AD crude product refining, including:
S5, the molten clear middle addition polar organic solvent that step S4 is obtained and basic salt, it is heated to reflux 1.5～3.5
Hour, adding activated carbon, sucking filtration, concentrating under reduced pressure goes out polar organic solvent, cooling, and centrifugation is washed
To 4-AD fine work.
Finally, if gained 4-AD fine work purity is defective, again purify, including:
S6, uses the 4-AD fine work obtained with the methanol soaking step S5 of 1.5～3.5 times of quality, directly
To 4-AD weight/mass percentage composition more than 98.5%.
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1
S1, takes the dehydroepiandros-sterone mother solution 100kg to obtain during 4-AD synthesis dehydroepiandros-sterone,
Add the toluene of 1000kg, at 50 DEG C after heating for dissolving, with 20kg methanol+180kg water+20kg hydrochloric acid
The acid solution molten clear pH value of regulation of composition is to 2, and 55 DEG C are stirred half an hour, separate lower layer of water, hot water wash upper liquid
It is 7 to pH；
S2, upper liquid step S1 obtained is heated to 112 DEG C, reflux dewatering, then is cooled to 80 DEG C,
Adding Ketohexamethylene, reflux dewatering to effluent is clarified；
S3, after dehydration, is cooled to 110 DEG C, adds aluminum isopropylate., is to slowly warm up to 114 DEG C, reaction
5h, sampling is done TLC point plate and is detected until reacting complete；
S4, after completion of the reaction, is cooled to 80 DEG C, adds NaOH aqueous solution, after reaction 1h, divides while hot
Leaving away except NaOH aqueous solution, use hot water wash reactant liquor, punching evaporates, and obtains 4-AD crude product；
S5, the molten clear middle methanol adding 8 times of volumes that step S4 is obtained and 3 to 4 kilograms of potassium carbonate,
Being heated to reflux 1.5 hours, add 10 kilograms of activated carbons, sucking filtration, concentrating under reduced pressure goes out the methanol of 7 times of volumes,
Cooling, centrifugation, washing obtains 4-AD fine work；
S6, uses the 4-AD fine work obtained with the methanol soaking step S5 of 1.5 times of quality, until
4-AD content reaches 98.5%.
Calculating final 4-AD recovery rate is 20%.
Embodiment 2
S1, takes the dehydroepiandros-sterone mother solution 100kg to obtain during 4-AD synthesis dehydroepiandros-sterone,
Add the ethyl acetate of 1000kg, at 50 DEG C after heating for dissolving, with 30 ethanol+280kg water+30kg salt
The acid solution molten clear pH value of regulation of acid composition is to 2.5, and 52 DEG C are stirred half an hour, separate lower layer of water, in hot water wash
Layer liquid is 6.5 to pH；
S2, upper liquid step S1 obtained is heated to 111 DEG C, reflux dewatering, then is cooled to 85 DEG C, adds
Entering Ketohexamethylene, reflux dewatering to effluent is clarified；
S3, after dehydration, is cooled to 105 DEG C, adds aluminum isopropylate., is to slowly warm up to 112 DEG C, reaction
6h, sampling is done TLC point plate and is detected until reacting complete；
S4, after completion of the reaction, is cooled to 85 DEG C, adds NaOH aqueous solution, after reaction 1.5h, while hot
Separating and remove NaOH aqueous solution, use hot water wash reactant liquor, punching evaporates, and obtains 4-AD crude product；
S5, the molten clear middle ethanol adding 10 times of volumes that step S4 is obtained and 5 kilograms of potassium carbonate, heating
Refluxing 2.5 hours, add 6 kilograms of activated carbons, sucking filtration, concentrating under reduced pressure goes out the ethanol of 9 times of volumes, cooling,
Centrifugation, washing obtains 4-AD fine work；
S6, uses the 4-AD fine work obtained with the methanol soaking step S5 of 2.5 times of quality, until
4-AD content reaches 98.5%.
Calculating final 4-AD recovery rate is 18%.
Embodiment 3
S1, takes the dehydroepiandros-sterone mother solution 100kg to obtain during 4-AD synthesis dehydroepiandros-sterone,
Add the ethyl acetate of 1000kg, at 55 DEG C after heating for dissolving, with 50 ethanol+480kg water+50kg salt
The acid solution molten clear pH value of regulation of acid composition is to 3, and 55 DEG C are stirred half an hour, separate lower layer of water, hot water wash upper strata
Liquid is 7 to pH；
S2, upper liquid step S1 obtained is heated to 112 DEG C, reflux dewatering, then is cooled to 90 DEG C,
Adding calcium hypochlorite, reflux dewatering to effluent is clarified；
S3, after dehydration, is cooled to 110 DEG C, adds aluminum isopropylate., is to slowly warm up to 114 DEG C, reaction
8h, sampling is done TLC point plate and is detected until reacting complete；
S4, after completion of the reaction, is cooled to 90 DEG C, adds NaOH aqueous solution, after reaction 2h, divides while hot
Leaving away except NaOH aqueous solution, use hot water wash reactant liquor, punching evaporates, and obtains 4-AD crude product；
S5, the molten clear middle ethanol adding 15 times of volumes that step S4 is obtained and 6 to 7 kilograms of potassium carbonate,
Being heated to reflux 1.5 hours, add 10 kilograms of activated carbons, sucking filtration, concentrating under reduced pressure goes out the ethanol of 14 times of volumes,
Cooling, centrifugation, washing obtains 4-AD fine work；
S6, uses the 4-AD fine work obtained with the methanol soaking step S5 of 3.5 times of quality, until
4-AD content reaches 98.5%.
Calculating final 4-AD recovery rate is 15%.
The present invention is not limited to above-mentioned embodiment, for those skilled in the art, not
On the premise of departing from the principle of the invention, it is also possible to making some improvements and modifications, these improvements and modifications are also considered as
Within protection scope of the present invention.The content not being described in detail in this specification belongs to this area professional technique people
The known prior art of member.
Claims (10)
1. the technique refining 4-AD from dehydroepiandros-sterone mother solution, it is characterised in that include with
Lower step:
S1, takes the dehydroepiandros-sterone mother solution to obtain during 4-AD synthesis dehydroepiandros-sterone, adds
Non-polar organic solvent, at 50～55 DEG C after heating for dissolving, with the acid solution molten clear pH value of regulation to 2～3, separates
Lower layer of water, hot water wash upper liquid to pH is 6～7；
S2, upper liquid step S1 obtained is heated to 110～112 DEG C, reflux dewatering, then is cooled to
80～90 DEG C, adding weak oxidant, reflux dewatering to effluent is clarified；
S3, after dehydration, is cooled to 100～110 DEG C, adds aluminum isopropylate., is to slowly warm up to 110～114 DEG C,
Reaction 5～8h, sampling is done TLC point plate and is detected until reacting complete；
S4, after completion of the reaction, is cooled to 80～90 DEG C, adds alkaline aqueous solution, after reaction 1～2h, while hot
Separating and remove alkaline aqueous solution, use hot water wash reactant liquor, punching evaporates, and obtains 4-AD crude product；
S5, the molten clear middle addition polar organic solvent that step S4 is obtained and basic salt, it is heated to reflux 1.5～3.5
Hour, adding activated carbon, sucking filtration, concentrating under reduced pressure goes out polar organic solvent, cooling, and centrifugation is washed
To 4-AD fine work.
2. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: in described step S1, in dehydroepiandros-sterone mother solution, dehydroepiandros-sterone isomer weight/mass percentage composition is
30%～40%.
3. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: in described step S1, non-polar organic solvent uses toluene, ethyl acetate or chloroform.
4. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: in described step S1, acid solution is the mixed solution of hydrochloric acid, methanol and water, and wherein, every 100kg goes
The mixing that hydrogen meter androsterone mother solution correspondence adds 20～50kg methanol, 180～480kg water and 20～50kg hydrochloric acid is molten
Liquid.
5. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: in described step S2, weak oxidant uses Ketohexamethylene or calcium hypochlorite.
6. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: after punching evaporates in described step S4, emptying water, add methanol and activated carbon, at 60～65 DEG C
Lower reflux decolour.
7. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: in described step S5, polar organic solvent uses methanol or ethanol.
8. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: described step S5 neutral and alkali salt uses potassium carbonate or sodium carbonate.
9. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, it is special
Levy and be: the molten clear corresponding polar organic solvent adding 5～15 volumes of each volume in described step S5,
Concentrating under reduced pressure goes out the polar organic solvent of 4～14 volumes.
10. the technique refining 4-AD as claimed in claim 1 from dehydroepiandros-sterone mother solution, its
It is characterised by: also include that step S6, the employing methanol soaking step S5 of 1.5～3.5 times of quality obtain
4-AD fine work, until 4-AD weight/mass percentage composition is more than 98.5%.
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| CN201610244536.7A CN105801648A (en) | 2016-04-19 | 2016-04-19 | Technology for refining 4-androstenedione from dehydroepiandrosterone mother solution |
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| CN201610244536.7A CN105801648A (en) | 2016-04-19 | 2016-04-19 | Technology for refining 4-androstenedione from dehydroepiandrosterone mother solution |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565807A (en) * | 2016-10-27 | 2017-04-19 | 湖北竹溪人福药业有限责任公司 | Method for separating DHEA and alpha-isomers thereof |
| CN106589032A (en) * | 2016-11-07 | 2017-04-26 | 华中药业股份有限公司 | Treatment method for methyltestosterone mother liquor |
| CN110885353A (en) * | 2019-12-04 | 2020-03-17 | 湖北竹溪人福药业有限责任公司 | Method for preparing abiraterone acetate intermediate from dehydroepiandrosterone mother liquor |
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| CN103724387A (en) * | 2013-11-19 | 2014-04-16 | 华中药业股份有限公司 | Improved synthetic method of hydroxyprogesterone |
| CN104693260B (en) * | 2015-03-23 | 2016-03-23 | 湖北竹溪人福药业有限责任公司 | A kind for the treatment of process of dehydroepiandros-sterone mother liquor thing |
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2016
- 2016-04-19 CN CN201610244536.7A patent/CN105801648A/en active Pending
Patent Citations (2)
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| CN103724387A (en) * | 2013-11-19 | 2014-04-16 | 华中药业股份有限公司 | Improved synthetic method of hydroxyprogesterone |
| CN104693260B (en) * | 2015-03-23 | 2016-03-23 | 湖北竹溪人福药业有限责任公司 | A kind for the treatment of process of dehydroepiandros-sterone mother liquor thing |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565807A (en) * | 2016-10-27 | 2017-04-19 | 湖北竹溪人福药业有限责任公司 | Method for separating DHEA and alpha-isomers thereof |
| CN106565807B (en) * | 2016-10-27 | 2018-03-13 | 湖北竹溪人福药业有限责任公司 | A kind of separation DHEA and its αisomer method |
| CN106589032A (en) * | 2016-11-07 | 2017-04-26 | 华中药业股份有限公司 | Treatment method for methyltestosterone mother liquor |
| CN110885353A (en) * | 2019-12-04 | 2020-03-17 | 湖北竹溪人福药业有限责任公司 | Method for preparing abiraterone acetate intermediate from dehydroepiandrosterone mother liquor |
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