CN107365340A - A kind of preparation method of the β diacetates of 3,5 estradiene 3,17 - Google Patents
A kind of preparation method of the β diacetates of 3,5 estradiene 3,17 Download PDFInfo
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- CN107365340A CN107365340A CN201710544016.2A CN201710544016A CN107365340A CN 107365340 A CN107365340 A CN 107365340A CN 201710544016 A CN201710544016 A CN 201710544016A CN 107365340 A CN107365340 A CN 107365340A
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- CN
- China
- Prior art keywords
- estradienes
- purity
- diacetate
- preparation
- isopropanol
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
- C07J1/0077—Ethers
Abstract
The present invention relates to one kind 3,5 estradienes 3, the preparation method of 17 β diacetates, nandrolone, a hydration p-methyl benzenesulfonic acid, isopropyl acetate and No. 15 magnetons are sequentially added into reactor, heating response in oil bath pan after logical condensed water, when system starts condensing reflux, isopropenyl acetate is slowly injected into；After reaction terminates, solvent is steamed；System cooling plus pyridine, are added dropwise isopropanol, white solid product precipitation to be had；Sub-cooled filters, and is cleaned with cold isopropanol；White solid product is collected, the β diacetate net products of 3,5 estradiene 3,17 are produced after drying.The present invention carries out carbonyl using one pot synthesis as substrate using nandrolone and acetylating hydroxyl groups are protected, sintetics；Technique is simple, mild condition, yield up to 85%, it is environmentally friendly.The product of synthesis has important application value in medicine, veterinary drug and pesticide field；It is the important as precursors medicine of Tibolone.
Description
Technical field
The present invention relates to a kind of synthesis of -3,17 β of 3,5- estradienes-diacetate class 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 in 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 synthesizes
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 to research and develop 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.It is lighter to the inhibition level of metakentrin, do 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 list in Holland first, in more than 80 country's listings.I
State 60 one full year of life above women up to more than 70,000,000, into climacteric women 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, mild condition, and yield is high
- 3,17 β of 3,5- estradienes-diacetate preparation method.
The implementation of the object of the invention is the preparation method of one kind 3,5- estradienes -3,17 β-diacetate, by elder generation
Order adds 4.8g nandrolones, 168mg a hydration p-methyl benzenesulfonic acid, 6.2mL isopropyl acetate into 250mL double-neck flasks afterwards
With No. 15 magnetons, after spherical condensation tube is led into condensed water from the bottom to top, reactor is placed in heating response in 120 DEG C of oil bath pans；
When system starts condensing reflux, 6.4mL isopropenyl acetates are slowly injected into reaction system with syringe, it is every with TLC
Detect and react every 30min；After reaction terminates, it is distilling apparatus to change condensation reflux unit, and 4.8mL solvents are steamed from reactor；
After distillation terminates, temperature of reaction system is down to 75-80 DEG C, 16.4mL pyridine is added to system；Again by temperature of reaction system
75 DEG C are down to, 9.6mL isopropanol is then added dropwise, has white solid product precipitation；After the completion of feeding intake, by reaction system
- 15 DEG C to -5 DEG C are cooled to, is then filtered with 500mL Buchner funnel, with cold 0 DEG C to 5 DEG C isopropanol wash products, cleaning
Twice, each 50mL；White solid product is collected, in vacuum drying chamber, after 50-60 DEG C of dry 2h, produces 3,5- female steroids two
The β of alkene-3,17-diacetate net product.
The present invention carries out carbonyl using one pot synthesis as substrate using nandrolone and acetylating hydroxyl groups are protected, 3,5- of synthesis female steroids two
The β of alkene-3,17-diacetate；Technique is simple, mild condition, yield up to 85%, it is environmentally friendly.The 3,5- estradienes of synthesis-
3,17 β-diacetate class steroid drugs has important application value in medicine, veterinary drug and pesticide field.The 3 of gained of the invention,
- 3,17 β of 5- estradienes-diacetate is the important as precursors medicine of Tibolone.
Embodiment
Sequentially addition nandrolone, a hydration p-methyl benzenesulfonic acid, isopropyl acetate and No. 15 into reactor of the invention
Magneton, lead to after condensed water heating response in oil bath pan, when system starts condensing reflux, be slowly injected into isopropenyl acetate；
After reaction terminates, solvent is steamed；System cooling plus pyridine, are added dropwise isopropanol, white solid product precipitation to be had；Sub-cooled is taken out
Filter, is cleaned with cold isopropanol；White solid product is collected, it is pure to produce 3,5- estradienes -3,17 β-diacetate after drying
Product.Reaction expression is
Spherical condensation tube leads to after condensed water from the bottom to top is placed in heating response in 120 DEG C of oil bath pans by double-neck flask, is double
Neck flask bottom is immersed in silicone oil, and submergence is silicone oil highly higher than reaction solution height in double-neck flask.
The purity of nandrolone used 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%.
Isopropenyl acetate is slowly injected into reaction system with syringe, is detected and reacted every 30min with TLC.15
Number magneton, magnetic stirring apparatus rotating speed is 500 turns/s.
The present invention is described in detail with specific embodiment below.
4.8g nandrolones, 168mg a hydration p-methyl benzenesulfonic acid, 6.2mL are sequentially added into 250mL double-neck flasks
Isopropyl acetate and No. 15 magnetons, will spherical condensation tube lead to condensed water from the bottom to top after reactor is placed in 120 DEG C of oil bath pans
Middle heating response.When system starts condensing reflux, 6.4mL isopropenyl acetic acid is slowly injected into reaction system with syringe
Ester, detected and reacted every 30min with TLC.After reaction terminates, it is distilling apparatus to change condensation reflux unit, is steamed from reactor
4.8mL solvent (equivalent to the inlet amount of nandrolone)；After distillation terminates, temperature of reaction system is down to 75-80 DEG C, in humidity province
Between 16.4mL pyridine is added in scope to system.Temperature of reaction system is down to 75 DEG C again, the different of 9.6mL is then added dropwise
Propyl alcohol, have white solid product precipitation.After the completion of feeding intake, reaction system is cooled to -15 DEG C to -5 DEG C, then uses 500mL
Buchner funnel filter, with cold 0 DEG C to 5 DEG C isopropanol wash products, cleaning twice, each 50mL；Collect white solid production
Thing, in vacuum drying chamber after 50-60 DEG C of dry 2h, 3,5- estradienes -3,17 β-diacetate net product is produced, yield is
85%.
Hydrogen nuclear magnetic resonance1H 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)；13C 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。
Claims (4)
1. one kind 3, the preparation method of 5- estradienes -3,17 β-diacetate, it is characterised in that：Sequentially to 250mL
4.8g nandrolones, 168mg a hydration p-methyl benzenesulfonic acid, 6.2mL isopropyl acetate and No. 15 magnetons are added in double-neck flask, will
After spherical condensation tube leads to condensed water from the bottom to top, reactor is placed in heating response in 120 DEG C of oil bath pans；When system starts to condense
During backflow, 6.4mL isopropenyl acetates are slowly injected into reaction system with syringe, are detected instead every 30min with TLC
Should；After reaction terminates, it is distilling apparatus to change condensation reflux unit, and 4.8mL solvents are steamed from reactor；, will after distillation terminates
Temperature of reaction system is down to 75-80 DEG C, and 16.4mL pyridine is added to system；Temperature of reaction system is down to 75 DEG C again, then
9.6mL isopropanol is added dropwise, has white solid product precipitation；After the completion of feeding intake, reaction system is cooled to -15 DEG C
To -5 DEG C, then filtered with 500mL Buchner funnel, with cold 0 DEG C to 5 DEG C isopropanol wash products, cleaned twice, every time
50mL；Collect white solid product, in vacuum drying chamber, after 50-60 DEG C of dry 2h, produce 3,5- estradienes -3,17 β -
Diacetate net product.
2. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exist
In：Double-neck flask bottom is immersed in silicone oil, and submergence is silicone oil highly higher than reaction solution height in double-neck flask.
3. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exist
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%.
4. a kind of preparation method of 3,5- estradienes -3,17 β-diacetate according to claim 1, its feature exist
In：No. 15 magnetons, magnetic stirring apparatus rotating speed are 500 turns/s.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710544016.2A CN107365340A (en) | 2017-07-05 | 2017-07-05 | A kind of preparation method of the β diacetates of 3,5 estradiene 3,17 |
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| CN201710544016.2A CN107365340A (en) | 2017-07-05 | 2017-07-05 | A kind of 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 (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6500669B1 (en) * | 1994-05-04 | 2002-12-31 | Massachusetts Institute Of Technology | Programmable genotoxic agents and uses therefor |
| 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
- 2017-07-05 CN CN201710544016.2A patent/CN107365340A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6500669B1 (en) * | 1994-05-04 | 2002-12-31 | Massachusetts Institute Of Technology | Programmable genotoxic agents and uses therefor |
| 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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