CN107082793B - The preparation method of Desogestrel important intermediate - Google Patents
The preparation method of Desogestrel important intermediate Download PDFInfo
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- CN107082793B CN107082793B CN201710455648.1A CN201710455648A CN107082793B CN 107082793 B CN107082793 B CN 107082793B CN 201710455648 A CN201710455648 A CN 201710455648A CN 107082793 B CN107082793 B CN 107082793B
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- desogestrel
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
Abstract
The invention discloses a kind of preparation methods of Desogestrel important intermediate, include the following steps: for compound (2) to be dissolved in solvent, then the mixed system of zinc halide, solvent and trialkoxy silane is added, reaction, then from reaction system, it collects intermediate (4), reaction condition of the present invention is mild, risk is extremely low, easy to operate.Simultaneous reactions yield greatly improves, and reaction step also has traditional two-step method to become one-step method.Product (4) are prepared with we are bright, greatly reduce production cost.The problems such as avoiding used reagent and big, unstable, by-product environmental pollution is serious intermediate product toxicity simultaneously is convenient for industrializing implementation.Reaction equation is as follows:
Description
Technical field
The present invention relates to a kind of new processes for preparing Desogestrel important intermediate.
Background technique
Desogestrel is the potent progestational hormone of a new generation, it is its effective component Etonogestrel in human body metabolism, and is relied on
Pregnene is strong to progesterone receptor affinity, there is reliable inhibition Effect of Ovulation, low to androgen receptor affinity, therefore only slight
Androgen and protein assimilating metabolic activity, no androgenic activity but has stronger antiestrogenic, to lipid metaboli without bad
It influences, human physiological metabolism is influenced small.Desogestrel is third generation novel contraceptive drug, and structural formula is as follows:
Currently, committed step is compound (2) through 17 carbonyls progress 1,2 additions acquisition addition products in existing technology
(3), target product then is obtained to 3 carbonyl ketal protection acidic hydrolysis.Its reaction equation is as follows:
If J.Amer.Chem.Soc., 1998,121:710-714 provides a kind of method for preparing Desogestrel, benefit
3 carbonyls are protected by dithioglycol with compound (2), are obtained followed by lithium metal, liquefied ammonia method removing ethylene thioketal
It obtains key compound (4).
The important intermediate passes through to the oxidations of 17 hydroxyls, then to 17 carbonyls using acetenyl lithium reagent progress 1,
2 additions obtain target product Desogestrel.During obtaining important intermediate compound (4), second is utilized in document report
This with stench is more toxic substance and expensive to two mercaptan simultaneously, reacts largely use lithium metal and liquefied ammonia in next step
Reaction removing ethylene thioketal is carried out under ultralow temperature.Lithium metal is expensive and has certain risk, and liquefied ammonia is to environment
Entire reaction condition is very harsh when polluting Datong District, needs anhydrous and oxygen-free low-temp reaction, limits its industrial use.Separately need to refer to
Out be removing ethylene thioketal during more apparent double-bond migration problem can occur, be specifically shown in down:
Wherein compound (4 ') is the by-product for removing ethylene thioketal process electronics transfer, and the ratio of itself and (4)
About 4:96.The substance and compound (4) polarity are very close, as recrystallization, column chromatograph in the way of traditional isolate and purify
The substance can not all be effectively removed.In conclusion the problem of committed step, limits its use in industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of Desogestrel important intermediate, to overcome the prior art to exist
Drawbacks described above.
The method of this method includes the following steps:
Compound (2) is dissolved in solvent, the mixed system of zinc halide, solvent and trialkoxy silane is then added ,-
20~60 DEG C, react 0.5~12.0h, then from reaction system, collect intermediate (4), as prepare Desogestrel it is important in
Mesosome；
The method of the collection intermediate (4), including adjust pH to neutral, layering, extract, washing, filtering, filtrate it is dense
Contracting step, yield can reach 95~99.5%；
Preferably, compound (2) is dissolved in the mixture that zinc halide, solvent and trialkoxy silane are added dropwise in solvent
System, time for adding are 10-20 minutes, then -20~60 DEG C of 0.5~12.0h of reaction；Reaction equation is as follows:
Wherein: X represents chlorine, bromine or iodine；
Preferably, the zinc halide is zinc chloride, zinc bromide or zinc iodide；
The anhydrous zinc halide is preferably anhydrous zinc chloride；
The trialkoxy silane is trimethoxy silane, triethoxysilane or tripropyl silane etc., preferably three
Methoxy silane or triethoxysilane；
The R is C1~C4Linear or branched alkyl group or phenyl；
The solvent is methylene chloride, 1,2- dichloroethanes, pentane, n-hexane, acetonitrile, dimethyl sulfoxide, toluene
Or dimethylbenzene more than one；
Used zinc halide is in the reaction 1~2.0:1 with the mole ratio of compound (2)；
Used trialkoxy silane is in the reaction 1~5:1 with the mole ratio of compound (2)；
Method used in the present invention has no any report, use property for Desogestrel important intermediate (4) preparation
The direct one-step method deoxidation and reduction acquisition target product of combination of matter stabilization, cheap trialkoxy silane, anhydrous zinc halide.
Reaction condition is mild during simultaneous reactions, risk is extremely low, easy to operate.No matter from atom economy angle, safety perspective
It is still all significantly better than from storage transport angles using traditional two step process methods with Costco Wholesale angle.
Surprisingly, additive anhydrous zinc halide is not used in deoxidation process and only uses tri-alkoxy silicon merely
When alkane, compound (2) is without any reaction.After additive anhydrous zinc halide is added, product yield is greatly improved.By three alcoxyls
Base silane is replaced by trialkylsilane and then finds that reaction rate is greatly reduced.It is the most key simultaneously thick as obtained by GC detection
Product do not have in target product (4) any (4 ') by-product to generate.Yield and the remote ultra-traditional technique of stereoselectivity.We are bright
The method reported avoids encountered in such compound traditional synthesis using a large amount of expensive and unstable metals
Organolithium reagent and odorant dithioglycol, simultaneous reactions yield greatly improve, and reaction step also has traditional two-step method
Become one-step method.Product (4) are prepared with we are bright, greatly reduce production cost.Simultaneously avoid used reagent and
The problems such as intermediate product toxicity is big, unstable, by-product environmental pollution is serious." three wastes " discharge significantly in its production technology
It reduces.This is that other methods are unable to reach.With it is of the present invention and the Desogestrel important intermediate that is prepared of method
(4) since its reaction condition is mild, react more complete, chemo-selective is high, its purity can reach 99% after simple purification
More than.The reagent used in entire reaction is all more easy to get, and simultaneous reactions high income, reaction condition is mild, solvent
It can recycle, thus be convenient for industrializing implementation.
Specific embodiment
It will be helpful to understand the present invention by implementation method in detail below, but be not intended to limit the contents of the present invention.
Embodiment 1
The preparation of 11- methylene -18- methyl female steroid -4- alkene (4):
One it is dry full of nitrogen be equipped with thermometer, reflux condensing tube, magnetic agitation 250mL there-necked flask in successively
Anhydrous zinc chloride (6.82g is added；Fw:136.30；50mmol), anhydrous methylene chloride 100mL, then by trimethoxy silane
(6.11g；Fw:122.20；It 50mmol) is added at one time in system, 20 DEG C of stirring 0.5h；
By compound (2) (15.02g；Fw:300.44；It 50mmol) is dissolved in methylene chloride 50mL, at -20 DEG C, is added dropwise to
In reaction system, time for adding is 10 minutes；Then -20 DEG C of stirring 12h；
Saturated sodium bicarbonate solution is added in reaction system, adjusts pH to neutrality, separates organic phase, water phase methylene chloride
It extracts, then merges organic phase and obtain faint yellow clear liquid, it is dry with anhydrous magnesium sulfate.It is concentrated under reduced pressure and removes solvent, through positive heptan after
- 40 DEG C of alkane recrystallize to obtain white solid 13.60g, yield: 95%, G/C content is greater than 99.0%, does not detect (4 ') isomers.
mp 91-92℃；1H NMR(CDCl3,400MHz)δ5.44(s,1H),4.93(s,1H),4.73(s,1H),3.79
(t, J=8.5Hz, 1H), 2.78 (d, J=12.2Hz, 1H), 2.27-2.14 (m, 3H), 2.09 (m, 1H), 1.92 (br, 3H),
1.65-1.45 (m, 4H), 1.58 (d, J=11.8Hz, 1H), 1.66-1.16 (m, 8H), 1.09 (m, 1H), 1.02 (t, J=
7.5Hz,3H),0.86(m,1H).
Embodiment 2
The preparation of 11- methylene -18- methyl female steroid -4- alkene (4):
One it is dry full of nitrogen be equipped with thermometer, reflux condensing tube, magnetic agitation 250mL there-necked flask in successively
Anhydrous zinc chloride (13.63g is added；Fw:136.30；100mmol), anhydrous 1,2- dichloroethanes 100mL, then by trimethoxy
Silane (54.99g；Fw:122.20；450mmol) it is added at one time 20 DEG C of stirring 0.5h in system；
By compound (2) (15.02g；Fw:300.44；50mmol) it is dissolved in 1,2- dichloroethanes 50mL, at 20 DEG C, drop
It adds in reaction system, time for adding is 20 minutes；
After being added dropwise, 60 DEG C of reaction 2h add to saturated sodium bicarbonate solution in reaction system, tune pH to neutrality,
Organic phase is separated, water phase is extracted with methylene chloride, is then merged organic phase and is obtained faint yellow clear liquid, dry with anhydrous magnesium sulfate.Subtract
Pressure concentration removes solvent, chromatographs to obtain white solid 14.18g through column after, yield: 99%, G/C content is greater than 99.0%, does not detect
(4 ') isomers out.
mp 91-92℃；1H NMR(CDCl3,400MHz)δ5.44(s,1H),4.93(s,1H),4.73(s,1H),3.79
(t, J=8.5Hz, 1H), 2.78 (d, J=12.2Hz, 1H), 2.27-2.14 (m, 3H), 2.09 (m, 1H), 1.92 (br, 3H),
1.65-1.45 (m, 4H), 1.58 (d, J=11.8Hz, 1H), 1.66-1.16 (m, 8H), 1.09 (m, 1H), 1.02 (t, J=
7.5Hz,3H),0.86(m,1H).
Embodiment 3
The preparation of 11- methylene -18- methyl female steroid -4- alkene (4):
One it is dry full of nitrogen be equipped with thermometer, reflux condensing tube, magnetic agitation 250mL there-necked flask in successively
Anhydrous zinc iodide (17.56g is added；Fw:319.20；55mmol), anhydrous methylene chloride 100mL, then by trimethoxy silane
(12.22g；Fw:122.20；It 100mmol) is added at one time in system, 20 DEG C of stirring 0.5h；
By compound (2) (15.02g；Fw:300.44；It 50mmol) is dissolved in methylene chloride 50mL, -20 DEG C are added dropwise to instead
It answers in system, time for adding is 20 minutes；
After being added dropwise, saturated sodium bicarbonate solution is added dropwise in reaction system by 20 DEG C of reaction 0.5h, adjusts pH into
Property, organic phase is separated, water phase is extracted with methylene chloride, is then merged organic phase and is obtained faint yellow clear liquid, dry with anhydrous magnesium sulfate.
It is concentrated under reduced pressure and removes solvent, chromatograph to obtain white solid 14.18g through column after, yield: 99%, G/C content is greater than 99.0%, does not examine
Measure (4 ') isomers.
mp 91-92℃；1H NMR(CDCl3,400MHz)δ5.44(s,1H),4.93(s,1H),4.73(s,1H),3.79
(t, J=8.5Hz, 1H), 2.78 (d, J=12.2Hz, 1H), 2.27-2.14 (m, 3H), 2.09 (m, 1H), 1.92 (br, 3H),
1.65-1.45 (m, 4H), 1.58 (d, J=11.8Hz, 1H), 1.66-1.16 (m, 8H), 1.09 (m, 1H), 1.02 (t, J=
7.5Hz,3H),0.86(m,1H).
Embodiment 4
The preparation of 11- methylene -18- methyl female steroid -4- alkene (4):
One it is dry full of nitrogen be equipped with thermometer, reflux condensing tube, magnetic agitation 250mL there-necked flask in successively
Anhydrous zinc iodide (17.56g is added；Fw:319.20；55mmol), anhydrous methylene chloride 100mL, then by triethoxysilane
(16.43g；Fw:164.27；It 100mmol) is added at one time in system, 20 DEG C of stirring 0.5h；
By compound (2) (15.02g；Fw:300.44；It 50mmol) is dissolved in methylene chloride 50mL, at -20 DEG C, is added dropwise to
In reaction system, time for adding is 10 minutes；
Then 20 DEG C of reaction 1.5h, saturated sodium bicarbonate solution is added in reaction system, is adjusted pH to neutrality, is separated organic
Phase, water phase are extracted with methylene chloride, are then merged organic phase and are obtained faint yellow clear liquid, dry with anhydrous magnesium sulfate.Reduced pressure removes
Solvent is removed, chromatographs to obtain white solid 14.18g through column after, yield: 99%, G/C content is greater than 99.0%, does not detect that (4 ') are different
Structure body.
mp 91-92℃；1H NMR(CDCl3,400MHz)δ5.44(s,1H),4.93(s,1H),4.73(s,1H),3.79
(t, J=8.5Hz, 1H), 2.78 (d, J=12.2Hz, 1H), 2.27-2.14 (m, 3H), 2.09 (m, 1H), 1.92 (br, 3H),
1.65-1.45 (m, 4H), 1.58 (d, J=11.8Hz, 1H), 1.66-1.16 (m, 8H), 1.09 (m, 1H), 1.02 (t, J=
7.5Hz,3H),0.86(m,1H)。
Claims (7)
1. the preparation method of Desogestrel important intermediate, which comprises the steps of:
Compound (2) is dissolved in solvent, the mixed system of zinc halide, solvent and trialkoxy silane is then added, is reacted,
Then it from reaction system, collects intermediate (4), as prepares Desogestrel important intermediate, reaction equation is as follows:
Wherein: X represents chlorine, bromine or iodine；
R is phenyl, trimethoxy silane base, triethoxysilicane alkyl or tripropyl silylation.
2. the method according to claim 1, wherein the method for the collection intermediate (4), including adjusting pH
To neutral, layering, extract, washing, filtering, filtrate concentration step.
3. the method according to claim 1, wherein compound (2) is dissolved in solvent be added dropwise to zinc halide,
The mixed system of solvent and trialkoxy silane, time for adding are 10-20 minutes.
4. the method according to claim 1, wherein the zinc halide is zinc chloride, zinc bromide or zinc iodide.
5. according to method described in claim 1, which is characterized in that the solvent is methylene chloride, 1,2- dichloroethanes, positive penta
Alkane, n-hexane, acetonitrile, dimethyl sulfoxide, toluene or dimethylbenzene more than one.
6. according to method described in claim 1, which is characterized in that used zinc halide gram with compound (2) in the reaction
Molecular proportion is 1~2.0:1；
Used trialkoxy silane is in the reaction 1~5:1 with the mole ratio of compound (2).
7. according to the described in any item methods of claim 1~6, which is characterized in that compound (2) is dissolved in solvent, then
The mixed system of zinc halide, solvent and trialkoxy silane is added, -20~60 DEG C, reacts 0.5~12.0h.
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| US3927046A (en) * | 1972-12-09 | 1975-12-16 | Akzona Inc | Novel 11,11-alkylidene steroids |
| US20130123523A1 (en) * | 2011-11-10 | 2013-05-16 | Klaus Nickisch | Methods for the preparation of etonogestrel and desogestrel |
| CN105237606B (en) * | 2014-07-11 | 2018-08-24 | 上海创诺制药有限公司 | It is a kind of to be used to synthesize intermediate of Desogestrel and its preparation method and application |
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Address after: Building No. 88 Chunhua Road, Jinshan Weizhen, Jinshan District, Shanghai, 201512 Patentee after: Shanghai Gongtuo Pharmaceutical & Chemical Industry Co., Ltd. Address before: Building No. 88 Chunhua Road, Jinshan Weizhen, Songjiang District, Shanghai, 201512 Patentee before: Shanghai Gongtuo Pharmaceutical & Chemical Industry Co., Ltd. |