CN105622702B - A kind of preparation method of CDB-2914 key intermediate - Google Patents
A kind of preparation method of CDB-2914 key intermediate Download PDFInfo
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- CN105622702B CN105622702B CN201610033185.5A CN201610033185A CN105622702B CN 105622702 B CN105622702 B CN 105622702B CN 201610033185 A CN201610033185 A CN 201610033185A CN 105622702 B CN105622702 B CN 105622702B
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- ethylenedioxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/008—Ketals at position 17
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Abstract
The present invention provides a kind of CDB-2914 key intermediate 3,3,20,20 pairs（Ethylenedioxy）The norpregna 9 of 17 α hydroxyls, 5,10 epoxy 19（11）The preparation method of alkene, step is as follows：By 3,3,20,20 pairs（Ethylenedioxy）The norpregna 5 of 17 α hydroxyls 19（10）,9（11）Diene is dissolved in dichloromethane, and ice bath is carried out under the conditions of pyridine, adds the hydrogen peroxide that anhydrous magnesium sulfate, hexachloroacetone and concentration are 30%, and the stirring reaction 1.5h under ice bath obtains 3,3,20,20 pairs（Ethylenedioxy）The norpregna 9 of 17 α hydroxyls, 5,10 epoxy 19（11）Alkene；By 3,3,20,20 pairs（Ethylenedioxy）The norpregna 9 of 17 α hydroxyls, 5,10 epoxy 19（11）Alkene, the frozen water containing five water sodium thiosulfate and dichloromethane hybrid reaction, then carry out a point liquid, extraction, washing, dry filter and are evaporated, produce 3,3,20,20 pairs（Ethylenedioxy）The norpregna 9 of 17 α hydroxyls, 5,10 epoxy 19（11）Alkene.The concentration of hydrogen peroxide is 30% used in the preparation method of the present invention, and potential safety hazard is small.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of CDB-2914 key intermediate 3,3,20,20 pairs
（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）The preparation method of alkene.
Background technology
During CDB-2914 is a kind of potent antiprogestin, building-up process, 3,3,20,20 pairs（Ethylenedioxy）-
17 Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）Alkene is key intermediate, United States Patent (USP) US4954490,
US5929262, Chinese patent 201110339479.8 is disclosed in CDB-2914 synthetic route, first by Material synthesis extremely
3,3,20,20 pairs, intermediate（Ethylenedioxy）- 17 Alpha-hydroxy -19- norpregnas -5（10）, 9（11）Diene, then by dioxygen
Water selective epoxidation obtains 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxy -19- norpregnas -9
（11）Alkene, this epoxidation process be CDB-2914 synthesis in important and crucial step, above-mentioned patent is in selective ring
50% hydrogen peroxide is employed in oxidation as oxidant.50% hydrogen peroxide has high-strength oxidisability, explosive and corrosion
Property, strong reaction during oxidation, production process security is low.
The content of the invention
The technical problem of solution：For the hydrogen peroxide concentration height used in existing CDB-2914 building-up process, deposit
In the shortcoming of potential safety hazard, the present invention provides a kind of CDB-2914 key intermediate 3,3,20,20 pairs（Ethylenedioxy）-
17 Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）The preparation method of alkene.
Technical scheme：A kind of CDB-2914 key intermediate 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxies-
5,10- epoxy -19- norpregnas -9（11）The step of preparation method of alkene, this method, is as follows：
The first step：By 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -19- norpregnas -5（10）,9（11）Diene
It is dissolved in dichloromethane, ice bath is carried out under the conditions of pyridine, anhydrous magnesium sulfate, hexachloroacetone and hydrogen peroxide is then added, in ice
The lower stirring reaction 1.5h of bath, obtains 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxy -19- norpregnas -9
（11）The concentration of alkene, wherein hydrogen peroxide is 30%；
Second step：By all 3,3,20,20 pairs prepared in the first step（Ethylenedioxy）- 17 Alpha-hydroxy -5,10-
Epoxy -19- norpregnas -9（11）Alkene, the frozen water containing five water sodium thiosulfate and dichloromethane hybrid reaction, are then carried out
Divide liquid, extraction, washing, dry filter and be evaporated, produce 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxies -
19- norpregnas -9（11）Alkene.
3,3,20,20 pairs in the first step described above（Ethylenedioxy）- 17 Alpha-hydroxy -19- norpregnas -5（10）,
9（11）Diene is 1.61g, and dichloromethane is 10mL, and pyridine is 40.82mL, and anhydrous magnesium sulfate is 2.41g, and hexachloroacetone is
151.89mL, hydrogen peroxide is 2.04mL.
Frozen water containing five water sodium thiosulfate in second step described above is 30 mL, wherein containing
5.96gNaS2O3·5H2O；Dichloromethane is 40mL.
Extract when being extracted in second step described above is dichloromethane.
Reagent in second step described above during dry filter is Na2SO4。
Beneficial effect：A kind of CDB-2914 key intermediate 3,3,20,20 pairs that the present invention is provided（Sub- second dioxy
Base）- 17 Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）The preparation method of alkene, the solvent of use, additive, reaction examination
Agent is the raw material being easy to get, and uses concentration for 30% hydrogen peroxide, reduces under the feed concentrations of hydrogen peroxide, condition of ice bath with nothing
Water magnesium sulfate is dehydrated, and is ensured the oxidisability of hydrogen peroxide in the reaction, is reduced the severe degree of oxidation reaction in synthesis, and contracts
The short time of oxidation reaction, the security of synthetic reaction process is improved, recovery rate is up to 64%.
Embodiment
3 used in following examples, 3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -19- norpregnas -5（10）,
9（11）Diene is purchased from Chengdu Yinuo Dabo Pharmaceutical Technology Co., Ltd..
Embodiment 1
A kind of CDB-2914 key intermediate 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxies -
19- norpregnas -9（11）The step of alkene, is as follows：
By the 3 of 1.61g, 3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -19- norpregnas -5（10）,9（11）Diene
It is dissolved in 10mL dichloromethane and 40.82mL pyridines, adds 2.41g anhydrous magnesium sulfate, ice bath adds 151.89mL chlordenes
Acetone and the H that 2.04mL concentration is 30%2O2, 1.5h is stirred under ice bath, 40mL dichloromethane is then added and contains
5.96gNaS2O3·5H2O frozen water 30mL, stirs 30min, and point liquid, dichloromethane is extracted once, washed once, and adds Na2SO4
Dry filter, is evaporated, and produces the 3 of 1.77g, 3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxies -19- go first
Pregnant steroid -9（11）Alkene.
3,3,20,20 pairs prepared in the present embodiment（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxies -19- are gone
The pregnant steroid -9 of first（11）The recovery rate of alkene is 64%.
Claims (5)
1. a kind of CDB-2914 key intermediate 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxies -
19- norpregnas -9（11）The preparation method of alkene, it is characterised in that as follows the step of this method：
The first step：By 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -19- norpregnas -5（10）,9（11）Diene is dissolved in
In dichloromethane, ice bath is carried out under the conditions of pyridine, anhydrous magnesium sulfate, hexachloroacetone and hydrogen peroxide are then added, under ice bath
Stirring reaction 1.5h, obtains 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）
The concentration of alkene, wherein hydrogen peroxide is 30%；
Second step：By all 3,3,20,20 pairs prepared in the first step（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- rings
Oxygen -19- norpregnas -9（11）Alkene, the frozen water containing five water sodium thiosulfate and dichloromethane hybrid reaction, are then divided
Liquid, extraction, washing, dry filter and it is evaporated, produces 3,3,20,20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -5,10- epoxies -
19- norpregnas -9（11）Alkene.
2. a kind of CDB-2914 key intermediate 3,3,20,20 pairs according to claim 1（Ethylenedioxy）-17
Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）The preparation method of alkene, it is characterised in that：3,3,20 in the first step,
20 pairs（Ethylenedioxy）- 17 Alpha-hydroxy -19- norpregnas -5（10）,9（11）Diene is 1.61g, and dichloromethane is 10mL,
Pyridine is 40.82mL, and anhydrous magnesium sulfate is 2.41g, and hexachloroacetone is 151.89mL, and hydrogen peroxide is 2.04mL.
3. a kind of CDB-2914 key intermediate 3,3,20,20 pairs according to claim 1（Ethylenedioxy）-17
Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）The preparation method of alkene, it is characterised in that：Contain five in the second step
The frozen water of water sodium thiosulfate is 30 mL, wherein containing 5.96gNaS2O3·5H2O；Dichloromethane is 40mL.
4. a kind of CDB-2914 key intermediate 3,3,20,20 pairs according to claim 1（Ethylenedioxy）-17
Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）The preparation method of alkene, it is characterised in that：When being extracted in the second step
Extract be dichloromethane.
5. a kind of CDB-2914 key intermediate 3,3,20,20 pairs according to claim 1（Ethylenedioxy）-17
Alpha-hydroxy -5,10- epoxy -19- norpregnas -9（11）The preparation method of alkene, it is characterised in that：It is dried in the second step
Reagent during filter is Na2SO4。
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| CN107629107B (en) * | 2017-11-10 | 2020-06-09 | 广州市桐晖药业有限公司 | Synthetic method of ulipristal acetate |
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| US5929262A (en) * | 1995-03-30 | 1999-07-27 | The United States Of America As Represented By The Department Of Health And Human Services | Method for preparing 17α-acetoxy-11β-(4-N, N-dimethylaminophyl)-19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates |
| CN102372760A (en) * | 2010-08-12 | 2012-03-14 | 杭州容立医药科技有限公司 | Synthesis method of progesterone receptor regulating agent ulipristal |
| CN103772468B (en) * | 2012-10-19 | 2017-04-05 | 华润紫竹药业有限公司 | The preparation method and purposes of acetic acid spy's plast ketone and its intermediate |
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Effective date of registration: 20191209 Address after: 215400 room 01, building 13, No.1, Zhaoyan Road, Shaxi Town, Taicang City, Suzhou City, Jiangsu Province Patentee after: Suzhou Xineng Environmental Protection Technology Co., Ltd Address before: 215000 KELONG Road, Suzhou New Technology Industrial Development Zone, Jiangsu, China, No. 28 Patentee before: Suzhou Health College |
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