CN105622702A - Preparation method of ulipristal acetate key intermediate - Google Patents
Preparation method of ulipristal acetate key intermediate Download PDFInfo
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- 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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- ethylenedioxy
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- norpregna
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- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 title claims abstract description 16
- 229960000499 ulipristal acetate Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 45
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001993 dienes Chemical class 0.000 claims abstract description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005457 ice water Substances 0.000 claims abstract description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 6
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000000605 extraction Methods 0.000 claims abstract 3
- 239000007788 liquid Substances 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 8
- MECNYBBLQSORDY-WBIRKVOGSA-N (8s,10s,13r,14s,17s)-17-ethyl-10,13-dimethyl-2,3,4,5,6,7,8,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1CCC[C@]2(C)C3=CC[C@]4(C)[C@@H](CC)CC[C@H]4[C@@H]3CCC21 MECNYBBLQSORDY-WBIRKVOGSA-N 0.000 claims description 5
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- -1 ethylenedioxy Chemical group 0.000 claims description 2
- 238000003756 stirring Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 4
- 238000006735 epoxidation reaction Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 1
- 230000000708 anti-progestin effect Effects 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
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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
本发明提供一种醋酸乌利司他关键中间体3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯的制备方法，步骤如下：将3,3,20,20双（亚乙二氧基）-17α-羟基-19-去甲孕甾-5（10）,9（11）二烯溶于二氯甲烷中，在吡啶条件下进行冰浴，加入无水硫酸镁、六氯丙酮和浓度为30％的双氧水，在冰浴下搅拌反应1.5h，得到3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯；将3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯、含有五水硫代硫酸钠的冰水和二氯甲烷混合反应，然后进行分液、萃取、洗涤、干燥过滤和蒸干，即得3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯。本发明的制备方法所用双氧水的浓度为30％，安全隐患小。The invention provides a key intermediate of ulipristal acetate 3,3,20,20 bis(ethylenedioxy)-17α-hydroxyl-5,10-epoxy-19-norpregna-9 (11 ) ene preparation method, the steps are as follows: 3,3,20,20 bis(ethylenedioxy)-17α-hydroxyl-19-norpregna-5(10),9(11) dienes are dissolved in In dichloromethane, carry out ice bath under the condition of pyridine, add anhydrous magnesium sulfate, hexachloroacetone and hydrogen peroxide with a concentration of 30%, stir and react under ice bath for 1.5h, and obtain 3,3,20,20 bis( ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)ene; 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy -5,10-epoxy-19-norpregna-9(11)ene, ice water containing sodium thiosulfate pentahydrate and dichloromethane mixed reaction, followed by liquid separation, extraction, washing, dry filtration and Evaporate to dryness to obtain 3,3,20,20 bis(ethylenedioxy)-17α-hydroxyl-5,10-epoxy-19-norpregna-9(11)ene. The concentration of hydrogen peroxide used in the preparation method of the invention is 30%, and the safety hazard is small.
Description
技术领域technical field
本发明属于医药技术领域，尤其涉及一种醋酸乌利司他关键中间体3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯的制备方法。The invention belongs to the technical field of medicine, and in particular relates to a key intermediate of ulipristal acetate 3,3,20,20 bis(ethylenedioxy)-17α-hydroxyl-5,10-epoxy-19-normethyl Process for the preparation of pregna-9(11)ene.
背景技术Background technique
醋酸乌利司他是一种强效的抗孕激素，合成过程中，3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯是关键中间体，美国专利US4954490,US5929262,中国专利201110339479.8公开了醋酸乌利司他合成路线中，均先将原料合成至中间体3,3,20，20双（亚乙二氧基）-17α-羟基-19-去甲孕甾-5（10），9（11）二烯，然后由双氧水选择性环氧化获得3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯，此环氧化过程是醋酸乌利司他的合成中重要和关键的步骤，上述专利在选择性环氧化中均采用了50％的双氧水作为氧化剂。50％双氧水具有高强的氧化性、爆炸性和腐蚀性，氧化时反应强烈，生产过程安全性低。Ulipristal acetate is a potent antiprogestin, during the synthesis, 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-nor Pregnene-9(11)ene is the key intermediate. U.S. Patent US4954490, US5929262, and Chinese Patent 201110339479.8 disclose that in the synthesis route of ulipristal acetate, the raw materials are first synthesized into intermediates 3, 3, 20, and 20 bis( Ethylenedioxy)-17α-hydroxy-19-norpregna-5(10), 9(11) dienes, followed by selective epoxidation with hydrogen peroxide to obtain 3,3,20,20 bis(ethylenedioxy Dioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)ene, this epoxidation process is an important and key step in the synthesis of ulipristal acetate, the above Patents have adopted 50% hydrogen peroxide as oxidizing agent in selective epoxidation. 50% hydrogen peroxide is highly oxidizing, explosive and corrosive, and reacts strongly during oxidation, resulting in low safety in the production process.
发明内容Contents of the invention
解决的技术问题：针对现有的醋酸乌利司他合成过程中使用的双氧水浓度高，存在安全隐患的缺点，本发明提供一种醋酸乌利司他关键中间体3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯的制备方法。Technical problem to be solved: Aiming at the disadvantages of high concentration of hydrogen peroxide used in the synthesis process of existing ulipristal acetate and potential safety hazards, the present invention provides a key intermediate of ulipristal acetate 3, 3, 20, 20 bis Process for the preparation of (ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)ene.
技术方案：一种醋酸乌利司他关键中间体3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯的制备方法，该方法的步骤如下：Technical solution: a key intermediate of ulipristal acetate 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9 (11 ) preparation method of alkenes, the steps of the method are as follows:
第一步：将3,3,20,20双（亚乙二氧基）-17α-羟基-19-去甲孕甾-5（10）,9（11）二烯溶于二氯甲烷中，在吡啶条件下进行冰浴，然后加入无水硫酸镁、六氯丙酮和双氧水，在冰浴下搅拌反应1.5h，得到3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯，其中双氧水的浓度为30％；Step 1: Dissolve 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-19-norpregna-5(10),9(11) diene in dichloromethane, Under the condition of pyridine, ice bath was carried out, then anhydrous magnesium sulfate, hexachloroacetone and hydrogen peroxide were added, and the reaction was stirred under ice bath for 1.5h to obtain 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy -5,10-epoxy-19-norpregn-9(11)ene in a hydrogen peroxide concentration of 30%;
第二步：将第一步中制备得到的全部3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯、含有五水硫代硫酸钠的冰水和二氯甲烷混合反应，然后进行分液、萃取、洗涤、干燥过滤和蒸干，即得3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯。The second step: all the 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9 (11 ) alkenes, ice water containing sodium thiosulfate pentahydrate and dichloromethane mixed reaction, and then separated, extracted, washed, dried and filtered and evaporated to dryness, that is, 3,3,20,20 bis(ethylenedioxy base)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)ene.
上述所述的第一步中3,3,20,20双（亚乙二氧基）-17α-羟基-19-去甲孕甾-5（10）,9（11）二烯为1.61g，二氯甲烷为10mL，吡啶为40.82mL，无水硫酸镁为2.41g，六氯丙酮为151.89mL，双氧水为2.04mL。1.61 g of 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-19-norpregna-5(10),9(11) diene in the first step described above, Dichloromethane was 10 mL, pyridine was 40.82 mL, anhydrous magnesium sulfate was 2.41 g, hexachloroacetone was 151.89 mL, and hydrogen peroxide was 2.04 mL.
上述所述的第二步中含有五水硫代硫酸钠的冰水为30mL，其中含有5.96gNaS2O3·5H2O；二氯甲烷为40mL。In the second step mentioned above, 30 mL of ice water containing sodium thiosulfate pentahydrate contained 5.96 g of NaS 2 O 3 ·5H 2 O; 40 mL of dichloromethane.
上述所述的第二步中萃取时的萃取液为二氯甲烷。The extract when extracting in the above-mentioned second step is dichloromethane.
上述所述的第二步中干燥过滤时的试剂为Na2SO4。The reagent for drying and filtering in the second step mentioned above is Na 2 SO 4 .
有益效果：本发明提供的一种醋酸乌利司他关键中间体3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯的制备方法，采用的溶剂、添加剂、反应试剂均为易得的原料，采用浓度为30％的双氧水，降低了双氧水的投料浓度，冰浴条件下以无水硫酸镁脱水，保障双氧水在反应中的氧化性，降低了合成中氧化反应的剧烈程度，并且缩短了氧化反应的时间，提高了合成反应过程的安全性，收得率高达64%。Beneficial effect: a key intermediate of ulipristal acetate provided by the present invention 3,3,20,20 bis(ethylenedioxy)-17α-hydroxyl-5,10-epoxy-19-norpregna The preparation method of -9(11)ene, the solvents, additives and reaction reagents used are all easy-to-obtain raw materials, and the hydrogen peroxide with a concentration of 30% is used to reduce the feeding concentration of hydrogen peroxide, and dehydrated with anhydrous magnesium sulfate under ice bath conditions , to ensure the oxidation of hydrogen peroxide in the reaction, reduce the intensity of the oxidation reaction in the synthesis, shorten the time of the oxidation reaction, improve the safety of the synthesis reaction process, and the yield is as high as 64%.
具体实施方式detailed description
以下实施例中使用的3,3,20，20双（亚乙二氧基）-17α-羟基-19-去甲孕甾-5（10）,9（11）二烯购于成都伊诺达博医药科技有限公司。The 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-19-norpregna-5(10),9(11) dienes used in the following examples were purchased from Yinuoda, Chengdu Bo Medical Technology Co., Ltd.
实施例1Example 1
一种醋酸乌利司他关键中间体3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯的步骤如下：A key intermediate of ulipristal acetate 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)ene Proceed as follows:
将1.61g的3,3,20，20双（亚乙二氧基）-17α-羟基-19-去甲孕甾-5（10）,9（11）二烯溶于10mL二氯甲烷和40.82mL吡啶中，加入2.41g的无水硫酸镁，冰浴，加入151.89mL六氯丙酮和2.04mL浓度为30％的H2O2，在冰浴下搅拌1.5h，然后加入40mL二氯甲烷和含有5.96gNaS2O3·5H2O的冰水30mL，搅拌30min，分液，二氯甲烷萃取一次，洗涤一次，加入Na2SO4干燥过滤，蒸干，即得1.77g的3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯。Dissolve 1.61 g of 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-19-norpregna-5(10),9(11) diene in 10 mL of dichloromethane and 40.82 In mL pyridine, add 2.41g of anhydrous magnesium sulfate, ice bath, add 151.89mL of hexachloroacetone and 2.04mL of 30% H 2 O 2 , stir for 1.5h under ice bath, then add 40mL of dichloromethane and 30 mL of ice water containing 5.96 g NaS 2 O 3 5H 2 O, stirred for 30 min, separated, extracted once with dichloromethane, washed once, added Na 2 SO 4 to dry and filter, and evaporated to dryness to obtain 1.77 g of 3,3, 20,20 Bis(ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)ene.
本实施例中制备得到的3,3,20,20双（亚乙二氧基）-17α-羟基-5,10-环氧-19-去甲孕甾-9（11）烯的收得率为64%。Yield of 3,3,20,20 bis(ethylenedioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)ene prepared in this example 64%.
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| 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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| 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 |
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Patent Citations (3)
| 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)
| 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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