CN105622702A - Preparation method of ulipristal acetate key intermediate - Google Patents

Preparation method of ulipristal acetate key intermediate Download PDF

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Publication number
CN105622702A
CN105622702A CN201610033185.5A CN201610033185A CN105622702A CN 105622702 A CN105622702 A CN 105622702A CN 201610033185 A CN201610033185 A CN 201610033185A CN 105622702 A CN105622702 A CN 105622702A
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hydroxy
ethylenedioxy
epoxy
norpregna
alpha
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CN105622702B (en
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胡颖
陈彦燕
张士磊
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Suzhou Xineng Environmental Protection Technology Co., Ltd
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Suzhou Vocational Health College
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Epoxy Compounds (AREA)

Abstract

The invention provides a preparation method of a ulipristal acetate key intermediate 3,3,20,20-bis(ethylenedioxy)-17alpha-hydroxy-5,10-epoxy-19-norpregn-9(11)ene. The preparation method comprises the following steps: dissolving 3,3,20,20-bis(ethylenedioxy)-17alpha-hydroxy-19-norpregn-5(10),9(11)diene in dichloromethane, carrying out treatment in an ice bath under pyridine conditions, adding anhydrous magnesium sulfate, hexachloroacetone and 30% oxydol, and stirring in the ice bath to react for 1.5 hours, thereby obtaining 3,3,20,20-bis(ethylenedioxy)-17alpha-hydroxy-5,10-epoxy-19-norpregn-9(11)ene; and mixing the 3,3,20,20-bis(ethylenedioxy)-17alpha-hydroxy-5,10-epoxy-19-norpregn-9(11)ene, sodium-thiosulfate-pentahydrate-containing ice water and dichloromethane to react, and carrying out skimming, extraction, washing, drying, filtration and drying by distillation to obtain the 3,3,20,20-bis(ethylenedioxy)-17alpha-hydroxy-5,10-epoxy-19-norpregn-9(11)ene. The concentration of the oxydol used in the preparation method is 30%, so the potential safety hazard is low.

Description

A kind of preparation method of CDB-2914 key intermediate
Technical field
The invention belongs to pharmaceutical technology field, particularly relate to a kind of 3,3,20,20 pairs of (ethylenedioxy)-17 Alpha-hydroxy-5 of CDB-2914 key intermediate, 10-epoxy-19-norpregna-9(11) preparation method of alkene.
Background technology
CDB-2914 is a kind of potent gestation, in building-up process, 3, 3, 20, 20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5, 10-epoxy-19-norpregna-9(11) alkene is key intermediate, US Patent No. 4954490, US5929262, Chinese patent 201110339479.8 discloses in CDB-2914 synthetic route, all first by Material synthesis to intermediate 3, 3, 20, 20 couples (ethylenedioxy)-17 Alpha-hydroxy-19-norpregna-5(10), 9(11) diene, then 3 are obtained by hydrogen peroxide selective epoxidation, 3, 20, 20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5, 10-epoxy-19-norpregna-9(11) alkene, this epoxidation process is step important and crucial in the synthesis of CDB-2914, above-mentioned patent all have employed the hydrogen peroxide of 50% as oxidant in selective epoxidation. 50% hydrogen peroxide has high-strength oxidisability, explosivity and corrosivity, strong reaction during oxidation, and production process safety is low.
Summary of the invention
Solve the technical problem that: high for the hydrogen peroxide concentration used in existing CDB-2914 building-up process, the shortcoming that there is 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-norpregna-9(11) preparation method of alkene.
Technical scheme: a kind of 3,3,20,20 pairs of (ethylenedioxy)-17 Alpha-hydroxy-5 of CDB-2914 key intermediate, 10-epoxy-19-norpregna-9(11) preparation method of alkene, the step of the method is as follows:
The first step: by 3,3,20,20 couples (ethylenedioxy)-17 Alpha-hydroxy-19-norpregna-5(10), 9(11) diene is dissolved in dichloromethane, carries out ice bath when pyridine, it is subsequently adding anhydrous magnesium sulfate, hexachloroacetone and hydrogen peroxide, under ice bath, stirring reaction 1.5h, obtains 3,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) alkene, wherein the concentration of hydrogen peroxide is 30%;
Second step: whole 3 will prepared in the first step, 3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) alkene, frozen water containing five water sodium thiosulfate and dichloromethane hybrid reaction, then carry out separatory, extraction, washing, dry filter and be evaporated, obtain 3,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) alkene.
3,3,20,20 couples (ethylenedioxy)-17 Alpha-hydroxy-19-norpregna-5(10 in the first step described above), 9(11) diene is 1.61g, and dichloromethane is 10mL, and pyridine is 40.82mL, anhydrous magnesium sulfate is 2.41g, and hexachloroacetone is 151.89mL, and hydrogen peroxide is 2.04mL.
In second step described above, the frozen water containing five water sodium thiosulfate is 30mL, wherein contains 5.96gNaS2O3��5H2O; Dichloromethane is 40mL.
Extract when extracting in second step described above is dichloromethane.
In second step described above, reagent during dry filter is Na2SO4��
Beneficial effect: a kind of CDB-2914 key intermediate 3 provided by the invention, 3, 20, 20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5, 10-epoxy-19-norpregna-9(11) preparation method of alkene, the solvent adopted, additive, reaction reagent is the raw material being easy to get, adopting concentration is the hydrogen peroxide of 30%, reduce the feed concentrations of hydrogen peroxide, with anhydrous magnesium sulfate dehydration under condition of ice bath, ensure hydrogen peroxide oxidisability in the reaction, reduce the severe degree of oxidation reaction in synthesis, and shorten the time of oxidation reaction, improve the safety of synthetic reaction process, recovery rate is up to 64%.
Detailed description of the invention
3,3,20,20 couples (ethylenedioxies)-17 Alpha-hydroxy-19-norpregna-5(10 used in following example), 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-epoxy-19-norpregna-9(11) step of alkene is as follows:
By the 3,3,20 of 1.61g, 20 couples (ethylenedioxy)-17 Alpha-hydroxy-19-norpregna-5(10), 9(11) diene is dissolved in 10mL dichloromethane and 40.82mL pyridine, adds the anhydrous magnesium sulfate of 2.41g, ice bath, adds 151.89mL hexachloroacetone and 2.04mL concentration is the H of 30%2O2, under ice bath, stir 1.5h, be subsequently adding 40mL dichloromethane and containing 5.96gNaS2O3��5H2The frozen water 30mL of O, stirs 30min, separatory, and once, washing once, adds Na to dichloromethane extraction2SO4Dry filter, is evaporated, and obtains 3,3,20,20 pairs (ethylenedioxies)-17 Alpha-hydroxy-5 of 1.77g, 10-epoxy-19-norpregna-9(11) alkene.
3,3,20,20 couples (ethylenedioxies)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11 prepared in the present embodiment) recovery rate of alkene is 64%.

Claims (5)

1. 3,3,20,20 pairs of (ethylenedioxy)-17 Alpha-hydroxy-5 of a CDB-2914 key intermediate, 10-epoxy-19-norpregna-9(11) preparation method of alkene, it is characterised in that the step of the method is as follows:
The first step: by 3,3,20,20 couples (ethylenedioxy)-17 Alpha-hydroxy-19-norpregna-5(10), 9(11) diene is dissolved in dichloromethane, carries out ice bath when pyridine, it is subsequently adding anhydrous magnesium sulfate, hexachloroacetone and hydrogen peroxide, under ice bath, stirring reaction 1.5h, obtains 3,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) alkene, wherein the concentration of hydrogen peroxide is 30%;
Second step: whole 3 will prepared in the first step, 3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) alkene, frozen water containing five water sodium thiosulfate and dichloromethane hybrid reaction, then carry out separatory, extraction, washing, dry filter and be evaporated, obtain 3,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) alkene.
2. a kind of CDB-2914 key intermediate 3 according to claim 1,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) preparation method of alkene, it is characterized in that: in the described first step 3,3,20,20 couples (ethylenedioxy)-17 Alpha-hydroxy-19-norpregna-5(10), 9(11) diene is 1.61g, dichloromethane is 10mL, and pyridine is 40.82mL, and anhydrous magnesium sulfate is 2.41g, hexachloroacetone is 151.89mL, and hydrogen peroxide is 2.04mL.
3. a kind of CDB-2914 key intermediate 3 according to claim 1,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) preparation method of alkene, it is characterized in that: in described second step, the frozen water containing five water sodium thiosulfate is 30mL, wherein contains 5.96gNaS2O3��5H2O; Dichloromethane is 40mL.
4. a kind of CDB-2914 key intermediate 3 according to claim 1,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) preparation method of alkene, it is characterised in that: extract when extracting in described second step is dichloromethane.
5. a kind of CDB-2914 key intermediate 3 according to claim 1,3,20,20 pairs (ethylenedioxy)-17 Alpha-hydroxy-5,10-epoxy-19-norpregna-9(11) preparation method of alkene, it is characterised in that: in described second step, reagent during dry filter is Na2SO4��
CN201610033185.5A 2016-01-19 2016-01-19 A kind of preparation method of CDB-2914 key intermediate Active CN105622702B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107629107A (en) * 2017-11-10 2018-01-26 广州市桐晖药业有限公司 A kind of synthetic method of CDB-2914

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030390A2 (en) * 1995-03-30 1996-10-03 The United States Of America, Represented By The Secretary, Department Of Health And Human Services METHOD FOR PREPARING 17α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-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
CN103772468A (en) * 2012-10-19 2014-05-07 华润紫竹药业有限公司 Preparation methods and purposes of Proellex(R)-V and intermediate of Proellex(R)-V

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030390A2 (en) * 1995-03-30 1996-10-03 The United States Of America, Represented By The Secretary, Department Of Health And Human Services METHOD FOR PREPARING 17α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-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
CN103772468A (en) * 2012-10-19 2014-05-07 华润紫竹药业有限公司 Preparation methods and purposes of Proellex(R)-V and intermediate of Proellex(R)-V

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107629107A (en) * 2017-11-10 2018-01-26 广州市桐晖药业有限公司 A kind of synthetic method of CDB-2914

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