CN107353318A - The preparation method of 6 dehydrogenation nandrolone acetates - Google Patents
The preparation method of 6 dehydrogenation nandrolone acetates Download PDFInfo
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- CN107353318A CN107353318A CN201710564057.8A CN201710564057A CN107353318A CN 107353318 A CN107353318 A CN 107353318A CN 201710564057 A CN201710564057 A CN 201710564057A CN 107353318 A CN107353318 A CN 107353318A
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- reaction
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- dehydrogenations
- 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
Abstract
Steroid drugs Tibolone is the medicine for treating climacteric or Post operation menopausal women disorder.It with the β diacetates of 3,5 estradiene 3,17 is that raw material is sloughed by bromine addition and completes the displacement of alkene that this route, which is, synthesizes 6 dehydrogenation nandrolone acetates, this medicine is one of important as precursors medicine of Tibolone, yield 85%.The invention provides simple and easy to operate, high yield 6 dehydrogenation nandrolone acetates steroid drugs of synthesis a method.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to the preparation method of 6- dehydrogenation nandrolone acetates 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 for treating climacteric or Post operation menopausal women disorder.Because of its tool
There are weak estrogen, progestational hormone sample activity.It can make the hypothalamic hypophyseal system of climacteric women stable, can substantially suppress blood plasma
Follicle-stimulating hormone (FSH) is horizontal.It is lighter to the inhibition level of metakentrin, prolactin(PRL is not influenceed, has suppression ovulation to make to the women of child-bearing age
With hormone replacement therapy (HRT) medicine being approved as quickly, for alleviating menopause symptom after postmenopausal women.Steroid drugs
Tibolone eliminates climacteric syndrome shape with its complementing estrogen, prevents from losing sad without causing uterus canceration and breast canceration
Outstanding advantages, turn into the choice drug for improving climacteric women quality of life.6- dehydrogenation nandrolone acetates are steroid drugs for vigorous
One of 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
The preparation method of 6- dehydrogenation nandrolone acetates.
A kind of preparation method of 6- dehydrogenations nandrolone acetate, its step are：In reaction vessel, by compound 3,5- female steroids
Diene -3,17 β-diacetate is dissolved in the mixed liquor of DMF and water, and at -10 DEG C to -5 DEG C, magnetic force stirs maintenance system reaction temperature
Mix, the NBS solution being dissolved in DMF is added dropwise, while maintenance reaction temperature after the completion of feeding intake, is warming up to 25 below 0 DEG C
DEG C, with TLC detections reaction, (TLC, which is otherwise known as, does thin-layered chromatography, and silica gel is coated on support plate, and silica gel is stationary phase, at this
We utilize reactant in organic phase and production by the use of properly mixed ethyl acetate and petroleum ether as solvent flow phase in secondary experiment
The polarity of thing is different, and absorption affinity is also different, so the different organic matters in organic phase will stop in the presence of solvent
Onboard different position.We are monitored whether reaction terminates using TLC during reaction, are inhaled respectively with capillary
Two raw materials and reaction solution are taken, liquid dot is equably got in suitable position on silica gel plate, deploys in cylinder is opened up, waits flowing
Suitable height is mutually climbed to, silica gel plate see whether that the point of product occurs under uviol lamp).Question response liquid is in TLC
On without raw material point occur thinking that reaction is completed.A certain amount of sodium carbonate is put into system first, treats that sodium carbonate is complete in reaction solution
After fully dissolved, then to a certain amount of sodium bromide of system input, after the completion of feeding intake, reaction system is warming up to 45 DEG C, maintains this
Temperature continues to react half an hour, then after being gradually heating to 80 DEG C, maintains this temperature to continue reaction a period of time until intermediate product
The i.e. reaction of 6- dehydrogenation nandrolone acetic acid esterified products is fully converted to terminate.Reaction stops heating after terminating, and reaction system is cooled down
To 25 DEG C, stop stirring, acetic acid aqueous solution (V is added to reaction systemAcetic acid：VWater=1：5), after the completion of addition, stirring reaction system
For a period of time, then add the acetic acid aqueous solution of equivalent, continue stirring reaction 12h, after after solid is separated out, not leaked with Bu Shi
Struggle against filtration product, cleans filter cake with the isopropanol of cold (0 DEG C to 5 DEG C) and the mixed liquor of purified water, obtains pale yellow powder, dries
Product produces 6- dehydrogenation nandrolone acetate net products to constant weight.
Preferably, the mass ratio between 3,5- estradienes -3,17 β-diacetate, DMF, water three is (15-20):
(50-70):1, preferably 16:60:1.
Preferably, NBS is dissolved in the DMF of 3 times of quality.
Preferably, the quality of sodium carbonate is the 5-10% of 3,5- estradienes -3,17 β-diacetate, preferably 5%.
Preferably, the quality of sodium bromide is the half of sodium carbonate.
Preferably, the concentration of acetic acid aqueous solution is VAcetic acid：VWater=1：5, mixing time is half after adding acetic acid solution for the first time
Hour.
Preferably, the heating in course of reaction uses oil bath heating, and reaction vessel bottom is immersed in silicone oil, submergence
It is that silicone oil is highly higher than reaction solution height in reaction vessel.
Preferably, the mass ratio of isopropyl alcohol and water is 2:3.
Preferably, the purity that the purity of 3,5- estradienes -3,17 β-diacetate is 98%, DMF is 99.5%, NBS
Purity is 99%, and the purity of sodium carbonate is 99.8%, and the purity of sodium bromide is 99%, and the purity of acetic acid is 99.5%, isopropanol
Purity be 99.7%.
Preferably, magnetic stirring apparatus rotating speed is 500 turns/s, but not limited to this scope, those skilled in the art can be according to need
It is adjusted rotating speed.
The advantages of the present invention：
The advantages that operation technique of the present invention is simple, mild condition, higher and environmentally friendly yield.The 6- of synthesis is gone
Hydrogen nandrolone acetates steroid drugs has important application value in medicine, veterinary drug and pesticide field.The steroid drugs is also
One of 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 is put into No. 8 magnetons in 100mL three-neck flask, by compound 3,5- estradienes -3,17 β -
Diacetate (1g) is dissolved in the mixed liquor of DMF (3.78g) and water (62mg), and maintenance system reaction temperature is at -10 DEG C to -5 DEG C.
At a temperature of this, be added dropwise NBS (0.535g) solution being dissolved in DMF (1.65g), at the same maintenance reaction temperature 0 DEG C with
Under.After the completion of feeding intake, mixture is warming up to 25 DEG C in 30min, detected and reacted with TLC.Question response complete after, first to
System input sodium carbonate (0.495g), sodium bromide (0.255g) is put into after abundant reaction, then to system, after the completion of feeding intake,
Reaction system is warming up to 40 DEG C, at this temperature maintenance reaction half an hour, then in one hour, is gradually heating to 80 DEG C,
Continue to react 3h until reaction terminates.Reaction stops heating after terminating, and reaction system is cooled into 25 DEG C, first to reaction system
Acetic acid aqueous solution (acetic acid 0.443g, water 2.775g) is added, the not stirring reaction liquid when adding, after the completion of addition, stirring reaction
System 5min, the acetic acid aqueous solution of equivalent is then added, continue to be stirred overnight.After gradually solid is separated out, with 500mL cloth
Family name's funnel filtration product, clean filter cake 3 times with the mixed liquor of cold isopropanol (0.2g) and purified water (0.3g), obtain faint yellow
Powder, desciccate to constant weight, produce 6- dehydrogenation nandrolone acetate net products, yield 85%.
It is the characterization result of product of the present invention below, it is recorded unanimously with document, and it is pure to be defined as 6- dehydrogenation nandrolone acetates
Product.
Fig. 1 is product proton nmr spectra1H NMR(400MHz,CDCl3):δ0.88(s,3H),1.10–1.18(m,1H),
1.20–1.34(m,3H),1.43–1.62(m,3H),1.80–1.83(m,2H),2.06(s,3H),2.12–2.39(m,6H),
2.52-2.56 (m, 1H), 4.65 (t, J=8.32Hz, 1H), 5.78 (s, 1H), 6.16-6.22 (m, 2H).
Fig. 2 is product carbon-13 nmr spectra13C NMR(100MHz,CDCl3):δ11.8,21.1,22.9,25.0,26.9,
27.3,36.4,37.7,40.8,41.1,43.4,45.9,47.7,82.1,124.4,128.8,141.4,158.8,171.1,
200.0。
Fig. 3 is product infrared spectrum IR (cm-1):1726,1652,1255,1117。
Claims (10)
- A kind of 1. preparation method of 6- dehydrogenations nandrolone acetate, it is characterised in that：In reaction vessel, by compound 3,5- female steroids Diene -3,17 β-diacetate is dissolved in the mixed liquor of DMF and water, and at -10 DEG C to -5 DEG C, magnetic force stirs maintenance system reaction temperature Mix, the NBS solution being dissolved in DMF is added dropwise, while maintenance reaction temperature after the completion of feeding intake, is warming up to 25 below 0 DEG C DEG C, detected and reacted with TLC, after question response is completed, put into a certain amount of sodium carbonate to system first, treat sodium carbonate in reaction solution In be completely dissolved after, then to system put into a certain amount of sodium bromide, after the completion of feeding intake, reaction system be warming up to 35-45 DEG C, Maintain this temperature to continue to react half an hour, after being gradually heating to 75-85 DEG C, maintain this temperature to continue to react, reaction stops after terminating Only heat, reaction system is cooled to 20-25 DEG C, stops stirring, the acetic acid that half volume is added to reaction system is water-soluble Liquid, after the completion of addition, stirring reaction system for a period of time, then adds the acetic acid aqueous solution of equivalent, continues stirring reaction 12h, after no longer solid is separated out, with filtered on buchner funnel product, the mixed liquor with 0 DEG C to 5 DEG C of isopropanol and purified water is clear Filter wash cake, pale yellow powder is obtained, desciccate to constant weight, produces 6- dehydrogenation nandrolone acetate net products.
- A kind of 2. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：3,5- female steroids two Mass ratio between the β of alkene-3,17-diacetate, DMF, water three is (15-20):(50-70):1, preferably 16:60:1.
- A kind of 3. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：NBS is dissolved in 3 In the DM F of times quality.
- A kind of 4. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：The matter of sodium carbonate Amount is the 5-10% of 3,5- estradienes -3,17 β-diacetate, preferably 5%.
- A kind of 5. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：The matter of sodium bromide Amount is the half of sodium carbonate.
- A kind of 6. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：Acetic acid aqueous solution Concentration be V acetic acid：V water=1：5, mixing time is half an hour after adding acetic acid solution for the first time.
- A kind of 7. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：In course of reaction Heating use oil bath heating, reaction vessel bottom is immersed in silicone oil, submergence be silicone oil highly be higher than reaction vessel in Reaction solution height.
- A kind of 8. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：Isopropyl alcohol and water Mass ratio be 2:3.
- A kind of 9. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：3,5- female steroids two The purity that the purity of alkene -3,17 β-diacetate is 98%, DMF is that 99.5%, NBS purity is 99%, and the purity of sodium carbonate is 99.8%, the purity of sodium bromide is 99%, and the purity of acetic acid is 99.5%, and the purity of isopropanol is 99.7%.
- A kind of 10. preparation method of 6- dehydrogenations nandrolone acetate according to claim 1, it is characterised in that：Magnetic agitation Device rotating speed is 500 turns/s.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047299A (en) * | 2017-12-29 | 2018-05-18 | 广西万德药业有限公司 | The preparation method of canrenone important intermediate |
| CN114634542A (en) * | 2022-03-30 | 2022-06-17 | 湖北武当安泰药业有限公司 | Preparation method of dehydronandrolone acetate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292285A (en) * | 2014-09-30 | 2015-01-21 | 湖北三晶生物科技有限公司 | Process for synthesizing high-content dehydronandrolon acetate |
| WO2015181116A1 (en) * | 2014-05-26 | 2015-12-03 | Crystal Pharma, S.A.U. | Process and intermediades for the preparation of 7-alkylated steroids |
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2017
- 2017-07-12 CN CN201710564057.8A patent/CN107353318A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015181116A1 (en) * | 2014-05-26 | 2015-12-03 | Crystal Pharma, S.A.U. | Process and intermediades for the preparation of 7-alkylated steroids |
| CN104292285A (en) * | 2014-09-30 | 2015-01-21 | 湖北三晶生物科技有限公司 | Process for synthesizing high-content dehydronandrolon acetate |
Non-Patent Citations (1)
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| 饶志威: "《脱氢诺龙醋酸酯的合成工艺研究》", 《中国药物化学杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047299A (en) * | 2017-12-29 | 2018-05-18 | 广西万德药业有限公司 | The preparation method of canrenone important intermediate |
| CN108047299B (en) * | 2017-12-29 | 2021-11-09 | 广西万德药业有限公司 | Preparation method of important intermediate of canrenone |
| CN114634542A (en) * | 2022-03-30 | 2022-06-17 | 湖北武当安泰药业有限公司 | Preparation method of dehydronandrolone acetate |
| CN114634542B (en) * | 2022-03-30 | 2022-11-25 | 湖北武当安泰药业有限公司 | Preparation method of dehydronandrolone acetate |
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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: 20190319 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: 20171117 |
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