CN107200762A - The preparation method of the β diacetates of 3,5 estradiene 3,17 - Google Patents
The preparation method of the β diacetates of 3,5 estradiene 3,17 Download PDFInfo
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- CN107200762A CN107200762A CN201710563782.3A CN201710563782A CN107200762A CN 107200762 A CN107200762 A CN 107200762A CN 201710563782 A CN201710563782 A CN 201710563782A CN 107200762 A CN107200762 A CN 107200762A
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- estradienes
- preparation
- diacetate
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- nandrolone
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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
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0074—Esters
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention belongs to technical field of medicine synthesis; it is specifically related to bright to be related to 3; 5 estradienes 3; the synthesis of 17 β diacetate class steroid drugs, synthetic route of the invention is that carbonyl and acetylating hydroxyl groups protection, synthesis 3 are carried out by substrate one pot synthesis of nandrolone; 5 estradienes 3; 17 β diacetates, this medicine is the important as precursors medicine of Tibolone, and yield is 90%.The invention provides simple and easy to operate, the high yield synthesis β diacetate class steroid drugs of 3,5 estradiene 3,17 a method.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to one kind 3,5- estradienes -3,17 β-diacetate class
The preparation method of steroid drugs.
Background technology
Steroid drugs plays a significant role in terms of disease preventing and treating, including medicine, veterinary drug and agricultural chemicals, what foreign countries had listed
Steroidal drug has a kind more than 400, the existing kind of China only account for thirdly point one, also have very big gap from advanced international standard,
In terms of steroid drugs research and development compared with advanced country in the world also a certain distance, be mainly shown as that steroid drugs is synthesized
Step is more, and reaction is complicated, and the distant effect of group is fairly obvious, and yield is low, particularly isolates and purifies difficulty.Many steroid drugs
The research of steroid drugs particularly with high content of technology goes research and development in China or blank, urgent need.
Steroid drugs Tibolone is the medicine that Dutch Ou Jianong (Organon) companies research and produce in the sixties in last century,
It is used to treat osteoporosis earliest.Because it has weak estrogen, progestational hormone sample activity.It can make the inferior colliculus of climacteric women
Pituitary system is stable, can substantially suppress blood plasma follicle-stimulating hormone (FSH) level.Inhibition level to metakentrin is lighter, does not influence
The women of child-bearing age are had suppression Effect of Ovulation by prolactin(PRL, hormone replacement therapy (HRT) medicine are approved as quickly, for alleviating
Menopause symptom after postmenopausal women.Organon companies in 1988 are first in Holland's listing, in more than 80 country's listings.I
State 60 one full year of life above women is up to more than 70,000,000, and the women into climacteric is more than 100,000,000 people.Steroid drugs Tibolone is mended with it
Fill estrogen and eliminate climacteric syndrome shape, prevent from losing the sad outstanding advantages without causing uterus canceration and breast canceration, into
To improve the choice drug of climacteric women quality of life.- 3,17 β of 3,5- estradienes-diacetate is steroid drugs for vigorous
The important as precursors medicine of dragon, the synthesis of the medicine is a committed step.
The content of the invention
The purpose of the present invention is to be directed to above-mentioned present situation, it is desirable to provide a kind of technical process is simple, and mild condition, yield is high
- 3,17 β of 3,5- estradienes-diacetate preparation method.
The preparation method of one kind 3,5- estradienes -3,17 β-diacetate, its step is sequentially to reactor
Interior addition nandrolone, a hydration p-methyl benzenesulfonic acid, isopropyl acetate, the heating response in magnetic agitation, 110-125 DEG C of oil bath pan,
When system starts condensing reflux, isopropenyl acetate is injected into reaction system with syringe, is detected and reacted with TLC, instead
After should terminating, distilled, steamed after partial solvent, temperature of reaction system is down to 75-80 DEG C, added to system a certain amount of
Pyridine, then temperature of reaction system is down to 65-75 DEG C, a certain amount of isopropanol is added dropwise, there is white solid product precipitation, throws
After the completion of material, reaction system is cooled to -15 DEG C to -5 DEG C, suction filtration is then carried out, with 0 DEG C to 5 DEG C of isopropanol wash products,
White solid product is collected, 3,5- estradienes -3,17 β-diacetate net product is produced after drying.
Further, wherein nandrolone, a hydration p-methyl benzenesulfonic acid, the mass ratio of isopropyl acetate are (20-40):1:
(110-120)。
It is preferred that, steam inlet amount of the amount equivalent to nandrolone of solvent.
It is preferred that, the addition quality of pyridine is the 1-5% of nandrolone.
It is preferred that, the addition quality of isopropanol is 1-3 times of nandrolone.
It is preferred that, detected and reacted every 30min with TLC, but this scope is not limited to, required according to accuracy of detection, can be appropriate
Detection time interval is reduced in increase.
It is preferred that, the temperature of oil bath pan is 120 DEG C.
It is preferred that, during oil bath heating, reactor bottom is immersed in silicone oil, and submergence is that silicone oil is highly higher than reactor
Interior reaction solution height.
It is preferred that, the purity of nandrolone is 98%, and the purity of a hydration p-methyl benzenesulfonic acid is 99%, and isopropyl acetate purity is
99%, the purity of isopropenyl acetate is 99%, and the purity of pyridine is 99.5%, and the purity of isopropanol is 99.7%.
It is preferred that, magnetic stirring apparatus rotating speed is 500 turns/s, but is not limited to this scope, is required, can suitably adjusted according to reaction
Rotating speed.
The advantages of the present invention：
Operation technique of the present invention is simple, mild condition, higher and environmentally friendly yield the advantages of.The 3,5- of synthesis
The β of estradiene-3,17-diacetate class steroid drugs has important application value in medicine, veterinary drug and pesticide field.The steroid
Body medicine is also the important as precursors medicine of Tibolone.
Brief description of the drawings
The proton nmr spectra of Fig. 1 products of the present invention；
The carbon-13 nmr spectra of Fig. 2 products of the present invention；
The infrared spectrum of Fig. 3 products of the present invention；
Wherein, proton nmr spectra INSTRUMENT MODEL：Bruker DPX-400,1H NMR(400MHz,CDCl3)；Nuclear magnetic resonance
Carbon composes INSTRUMENT MODEL：Bruker DPX-400,13C NMR(100MHz,CDCl3)；Infrared spectrum
INSTRUMENT MODEL：Nicolet IS50FT-IR.
Embodiment
The present invention reaction expression be
The present invention sequentially adds 4.8g nandrolones, 168mg a hydration to toluene sulphur in 250mL double-neck flasks
Acid, 6.2mL isopropyl acetate and No. 15 magnetons, will be placed in 120 after spherical condensation tube from the bottom to top logical condensed water by reactor
Heating response in DEG C oil bath pan.When system starts condensing reflux, 6.4mL isopropyls are slowly injected into reaction system with syringe
Alkenyl acetate, is detected every 30min with TLC and reacted.After reaction terminates, change condensation reflux unit for distilling apparatus, steam 2 bodies
Long-pending solvent (equivalent to the inlet amount of nandrolone).After distillation terminates, temperature of reaction system is down to 75-80 DEG C, in temperature range
16.4mL pyridine is added in scope to system.Temperature of reaction system is down to 75 DEG C again, 9.6mL isopropyl is then added dropwise
Alcohol, has white solid product precipitation.After the completion of feeding intake, reaction system is cooled to -5 DEG C, then with 500mL Buchner funnel
Suction filtration, with cold isopropanol wash products (50mL*2 times).Collect white solid product, dry after produce 3,5- estradienes-
3,17 β-diacetate net product, yield is 90%.
The following is the characterization result of product of the present invention, it records consistent with document, be defined as 3,5- estradienes -3,17 β -
Diacetate sterling.
Fig. 1 is product proton nmr spectra1H NMR(400MHz,CDCl3):δ0.82(s,3H),0.90–0.99(m,1H),
1.07–1.16(m,1H),1.18–1.28(m,3H),1.31–1.38(m,1H),1.43–1.56(m,2H),1.60–1.73(m,
2H),1.76–1.78(m,1H),1.86–1.92(m,2H),2.04(s,3H),2.07–2.11(m,1H),2.13(s,3H),
2.15-2.22 (m, 3H), 2.43-2.49 (m, 1H), 4.62 (t, J=8.44Hz, 1H), 5.47 (s, 1H), 5.76-5.77 (m,
1H)。
Fig. 2 is carbon-13 nmr spectra13C NMR(100MHz,CDCl3):δ11.9,21.1,21.2,23.3,26.2,27.2,
27.5,28.0,30.9,36.6,36.6,40.6,42.6,43.5,50.3,82.8,117.6,123.7,134.6,148.7,
169.2,171.2。
Fig. 3 is infrared spectrum IR (cm-1):1737,1656,1248,1202,1126。
Claims (10)
1. one kind 3, the preparation method of 5- estradienes -3,17 β-diacetate, it is characterised in that：Sequentially to reactor
Interior addition nandrolone, a hydration p-methyl benzenesulfonic acid, isopropyl acetate, the heating response in magnetic agitation, 110-125 DEG C of oil bath pan,
When system starts condensing reflux, isopropenyl acetate is injected into reaction system with syringe, is detected and reacted with TLC, instead
After should terminating, distilled, steamed after partial solvent, temperature of reaction system is down to 75-80 DEG C, added to system a certain amount of
Pyridine, then temperature of reaction system is down to 65-75 DEG C, a certain amount of isopropanol is added dropwise, there is white solid product precipitation, throws
After the completion of material, reaction system is cooled to -15 DEG C to -5 DEG C, suction filtration is then carried out, with 0 DEG C to 5 DEG C of isopropanol wash products,
White solid product is collected, 3,5- estradienes -3,17 β-diacetate net product is produced after drying.
2. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：Wherein nandrolone, a hydration p-methyl benzenesulfonic acid, isopropyl acetate, the mass ratio of isopropenyl acetate are (20-40):1:
(110-120):(30-35)。
3. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：Steam inlet amount of the amount equivalent to nandrolone of solvent.
4. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：The addition quality of pyridine is the 1-5% of nandrolone, preferably 2.5%.
5. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：The addition quality of isopropanol is 1-3 times of nandrolone, preferably 1.57.
6. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：Detected and reacted every 30min with TLC.
7. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：The temperature of oil bath pan is 120 DEG C.
8. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：During oil bath heating, reactor bottom is immersed in silicone oil, and submergence is that silicone oil is highly high higher than reaction solution in reactor
Degree.
9. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：The purity of nandrolone is 98%, and the purity of a hydration p-methyl benzenesulfonic acid is 99%, and isopropyl acetate purity is 99%, isopropyl alkene
The purity of base acetate is 99%, and the purity of pyridine is 99.5%, and the purity of isopropanol is 99.7%.
10. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exists
In：Magnetic stirring apparatus rotating speed is 500 turns/s.
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| CN201710563782.3A CN107200762A (en) | 2017-07-12 | 2017-07-12 | The preparation method of the β diacetates of 3,5 estradiene 3,17 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045617A (en) * | 2021-03-29 | 2021-06-29 | 湖北共同药业股份有限公司 | Preparation method of 3, 5-estradiene-3, 17 beta-diacetate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1780849A (en) * | 2003-03-04 | 2006-05-31 | 雷索卢蒂恩化学品有限公司 | Process for the production of tibolone |
| WO2015181116A1 (en) * | 2014-05-26 | 2015-12-03 | Crystal Pharma, S.A.U. | Process and intermediades for the preparation of 7-alkylated steroids |
-
2017
- 2017-07-12 CN CN201710563782.3A patent/CN107200762A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1780849A (en) * | 2003-03-04 | 2006-05-31 | 雷索卢蒂恩化学品有限公司 | Process for the production of tibolone |
| WO2015181116A1 (en) * | 2014-05-26 | 2015-12-03 | Crystal Pharma, S.A.U. | Process and intermediades for the preparation of 7-alkylated steroids |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045617A (en) * | 2021-03-29 | 2021-06-29 | 湖北共同药业股份有限公司 | Preparation method of 3, 5-estradiene-3, 17 beta-diacetate |
| CN113045617B (en) * | 2021-03-29 | 2023-11-24 | 湖北共同药业股份有限公司 | Preparation method of 3, 5-estradiene-3, 17 beta-diacetate |
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Effective date of registration: 20181205 Address after: 442700 Baiguoshu Lute No. 1, Shuidu Industrial Park, Danjiangkou Economic Development Zone, Shiyan City, Hubei Province Applicant after: Hubei Gongtong Biological Science & Technology Co., Ltd. Address before: 442700 Baiguoshu Lute No. 1, Shuidu Industrial Park, Danjiangkou Economic Development Zone, Shiyan City, Hubei Province Applicant before: Hubei Gongtong Biological Science & Technology Co., Ltd. Applicant before: Hubei Industry University |
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Effective date of registration: 20190325 Address after: 441400 Gaokeng Group, Xiaohe Town, Yicheng City, Xiangfan City, Hubei Province Applicant after: Hubei Common Pharmaceutical Co., Ltd. Address before: 442700 Baiguoshu Lute No. 1, Shuidu Industrial Park, Danjiangkou Economic Development Zone, Shiyan City, Hubei Province Applicant before: Hubei Gongtong Biological Science & Technology Co., Ltd. |
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Application publication date: 20170926 |