CN103319558A - Steroid compound, preparation method and uses thereof - Google Patents
Steroid compound, preparation method and uses thereof Download PDFInfo
- Publication number
- CN103319558A CN103319558A CN2012100776070A CN201210077607A CN103319558A CN 103319558 A CN103319558 A CN 103319558A CN 2012100776070 A CN2012100776070 A CN 2012100776070A CN 201210077607 A CN201210077607 A CN 201210077607A CN 103319558 A CN103319558 A CN 103319558A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- gestodene
- reaction
- steroidal compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention provides a gestodene intermediate and a preparation method thereof, and further provides a new process route for preparing gestodene. According to the present invention, phenylsulfinyl is introduced to the site 16 of a steroid etherate to obtain an easily-separated new compound, wherein characteristics of simple operation and high yield are provided when the compound is used for preparing gestodene.
Description
Technical field
The present invention relates to steroidal compounds and the application in preparation gestodene process thereof.
Background technology
Gestodene is present comparatively desirable third generation contraceptive bian, and its progestogen action is strong, and without male sex hormone and estrogen activity.Reliable for effect when this medicine is used for contraception, security good, the composite sheet of existing clinical itself and ethinylestradiol commonly used is as Short-term effective oral contraceptives.
Patent EP1586579 discloses a kind of synthetic method of gestodene; this method is take ethyl diketone compound (I) as starting raw material; by 3 carbonyls being carried out the ketal protection; then 16 reactive hydrogens are replaced; eliminate substituting group and form 15 (16) two keys; through 17 carbonyl ethinylations, last 3 deprotections make gestodene (V) again, its reaction process as shown in Scheme 1:
[route 1]
Above-mentioned preparation method's shortcoming is mainly: 16-benzenesulfinyl Betamethasone Ketal structures (VII) is oily mixture, can only separate by the method for column chromatography, is unfavorable for suitability for industrialized production; Ketal protected group is difficult for leaving away, and yield was lower when deprotection prepared gestodene under sour condition.
Summary of the invention
One of purpose of the present invention is for providing a kind of new steroidal compounds, and the preparation method of this compound.
Purpose of the present invention two for the purposes of this steroidal compounds in preparation gestodene process is provided.
New steroidal compounds, its structural formula is as follows:
Compound III
Compound III is made by 3-oxyethyl group-13 β-ethyl pregnant steroid-3 (4), 5 (6)-dienes-17-ketone (II) and the reaction of benzene sulfurous acid methyl esters.
Compound I I is made by the etherification protection of ethyl diketone compound (I) by 3 carbonyls.
Compound I can be bought in market and obtain.
Steroidal compounds of the present invention can be used for preparing gestodene and intermediate thereof.
The invention provides a kind of preparation method of new gestodene, the method comprises reaction as shown in Scheme 2:
[route 2]
Compound IV can be used as the intermediate of preparation gestodene, can adopt that disclosed method further prepares gestodene by compound IV in the document EP 2354150.
Specifically, above-mentioned steps of the present invention can be realized by following reaction:
1) 16 of compound I I reactive hydrogens replace, and obtain compound III:
Compound I I and organic solvent are joined in the reaction vessel, add alkali, under 15-30 ℃ of temperature, reacted 0.5~1 hour, add again benzene sulfurous acid methyl esters, after the tlc detection reaction is complete, add purified water, separate out a large amount of yellow solids, then filter, dry to get compound III.Wherein, described organic solvent is selected from tetrahydrofuran (THF), methylene dichloride, 1,2-methylene dichloride, N, dinethylformamide, ether and methyl-tert butanols ether, preferred tetrahydrofuran (THF); Selected alkali comprises sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, sodium amide, sodium hydride, potassium tert.-butoxide, n-Butyl Lithium and tert-butyl lithium etc., preferred potassium tert.-butoxide.
2) 16 bit substituents of compound III are eliminated, and form 15 (16) double bond compound IV:
Compound III and organic solvent are joined in the reaction vessel, under 15~30 ℃ of temperature, add alkali, then slowly be warming up to the solvent refluxing temperature, and every interval 0.5~1.5h continues to add alkali, reaction 4~6h, after the tlc detection reaction is complete, the concentrated faint yellow solid IV crude product that to get.To above-mentioned crude product normal pressure column chromatography for separation, dry behind the merging target product at last, obtain the compound IV sterling.Wherein, selected organic solvent comprises toluene, dimethylbenzene, dithiocarbonic anhydride etc., preferred toluene; Selected alkali comprises triethylamine, diethylamine, Tetramethyl Ethylene Diamine, n-Butyl Amine 99, hexahydroaniline, Tributylamine, quadrol etc., preferred triethylamine.
Beneficial effect of the present invention is:
1, using steroidal compounds of the present invention, to prepare the simple for process and yield of gestodene higher.
2, the 16-benzenesulfinyl etherate (III) for preparing can directly separate by the method for elutriation; having overcome 16-benzenesulfinyl Betamethasone Ketal structures of the prior art can only be by the shortcoming of column chromatography for separation; be not only applicable to laboratory study, more be conducive to industrialized amplification production.
Embodiment
Embodiment 1: the preparation of compound I I
Compound I 10g (34.92mmol) and 10mL dehydrated alcohol add triethyl orthoformate 10ml and tosic acid 0.2g in the lower stirring of room temperature (17 ℃), behind the stirring reaction 1h, and stopped reaction.Carry out column chromatography for separation with ethyl acetate/petroleum ether (2: 8), making product (compound I I) weight is 7.28g, and molar yield is 80.0%.
Embodiment 2: the preparation of compound III
Compound I I 7g (22.26mmol) mixes with the 100mL tetrahydrofuran (THF), and the lower potassium tert.-butoxide 8.51g that adds of room temperature (15 ℃) stirs the lower benzene sulfurous acid methyl esters 10mL that adds, behind the stirring reaction 2h, and stopped reaction.Elutriation obtains yellow solid (compound III), dries rear heavy 7.32g, and molar yield is 69.5%.
The MS of compound III (m/z): 438[M]+, 1H-NMR (CDCl3), δ 0.92 (3H, t, 18-CH3), δ 1.32 (3H, t, 3-CH3), δ 3.87 (2H, q, 3-CH2-O), δ 4.89 (1H, dt, H-6), δ 4.92 (1H, d, H-4), δ 7.41-7.58 (5H, m, 16-Ph); 13C-NMR, 209.7 (C-17), 155.2 (C-3), 135.9 (C-5), 123.4 (C-6), 102.1 (C-4), 73.7 (C-16), 62.3 (3-CH2-O).
Embodiment 3: the preparation of compound III
Compound I I 7g (22.26mmol) mixes with the 100mL methylene dichloride, and the lower potassium hydroxide 3.50g that adds of room temperature (20 ℃) stirs the lower benzene sulfurous acid methyl esters 10mL that adds, behind the stirring reaction 2h, and stopped reaction.Elutriation obtains yellow solid (compound III), dries rear heavy 6.88g, and molar yield is 65.3%.
The MS of compound III (m/z): 438[M]
+, 1H-NMR (CDCl
3), δ 0.92 (3H, t, 18-CH
3), δ 1.32 (3H, t, 3-CH
3), δ 3.87 (2H, q, 3-CH
2-O), δ 4.89 (1H, dt, H-6), δ 4.92 (1H, d, H-4), δ 7.41-7.58 (5H, m, 16-Ph); 13C-NMR, 209.7 (C-17), 155.2 (C-3), 135.9 (C-5), 123.4 (C-6), 102.1 (C-4), 73.7 (C-16), 62.3 (3-CH
2-O).
Embodiment 4: the preparation of compound III
Compound I I 7g (22.26mmol) mixes with 100mL N, dinethylformamide, and the lower potassium tert.-butoxide 8.51g that adds of room temperature (30 ℃) stirs the lower benzene sulfurous acid methyl esters 10mL that adds, behind the stirring reaction 2h, and stopped reaction.Elutriation obtains yellow solid (compound III), dries rear heavy 6.95g, and molar yield is 66.0%.
The MS of compound III (m/z): 438[M]
+, 1H-NMR (CDCl
3), δ 0.92 (3H, t, 18-CH
3), δ 1.32 (3H, t, 3-CH
3), δ 3.87 (2H, q, 3-CH
2-O), δ 4.89 (1H, dt, H-6), δ 4.92 (1H, d, H-4), δ 7.41-7.58 (5H, m, 16-Ph); 13C-NMR, 209.7 (C-17), 155.2 (C-3), 135.9 (C-5), 123.4 (C-6), 102.1 (C-4), 73.7 (C-16), 62.3 (3-CH
2-O).
Embodiment 5: the preparation of compound IV
Compound III 7g (15.96mmol) mixes with the 140mL toluene solution, and the lower 14mL triethylamine that adds of room temperature (15 ℃) slowly is warming up to backflow, continues reaction, and every interval 1h adds the 14mL triethylamine, constantly stirs, and the 5h afterreaction is complete.Carry out column chromatography for separation with ethyl acetate/petroleum ether (2: 8) after reaction solution is concentrated, obtain at last 4.41g product (compound IV), molar yield is 88.2%.
Embodiment 6: the preparation of compound IV
Compound III 7g (15.96mmol) mixes with the 140mL benzole soln, and the lower 8mL quadrol that adds of room temperature (30 ℃) slowly is warming up to backflow, continues reaction, and every interval 1h adds the 8mL quadrol, constantly stirs, and the 5h afterreaction is complete.Carry out column chromatography for separation with ethyl acetate/petroleum ether (2: 8) after reaction solution is concentrated, obtain at last 3.86g product (compound IV), molar yield is 77.2%.
Claims (8)
2. the preparation method of steroidal compounds claimed in claim 1 is characterized by the reaction of compound I I:3-oxyethyl group-13 β-ethyl pregnant steroid-3 (4), 5 (6)-dienes-17-ketone and benzene sulfurous acid methyl esters and makes.
3. preparation method according to claim 2 is characterized by and adds highly basic in the reaction, and organic solvent is selected from tetrahydrofuran (THF), methylene dichloride, 1,2-methylene dichloride, N, dinethylformamide, ether and methyl-tert butanols ether.
4. preparation method according to claim 3 is characterized by used highly basic and is selected from sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, sodium amide, sodium hydride, potassium tert.-butoxide, n-Butyl Lithium and tert-butyl lithium.
5. the purposes of steroidal compounds claimed in claim 1 is characterized by for the preparation of gestodene.
7. purposes according to claim 6 is characterized by and adds alkali in the preparation feedback, and organic solvent is selected from toluene, dimethylbenzene and dithiocarbonic anhydride.
8. purposes according to claim 7 is characterized by used alkali and is selected from triethylamine, diethylamine, Tetramethyl Ethylene Diamine, n-Butyl Amine 99, hexahydroaniline, Tributylamine and quadrol.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210077607.0A CN103319558B (en) | 2012-03-22 | 2012-03-22 | Steroidal compounds and its production and use |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210077607.0A CN103319558B (en) | 2012-03-22 | 2012-03-22 | Steroidal compounds and its production and use |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103319558A true CN103319558A (en) | 2013-09-25 |
CN103319558B CN103319558B (en) | 2016-01-20 |
Family
ID=49188643
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210077607.0A Active CN103319558B (en) | 2012-03-22 | 2012-03-22 | Steroidal compounds and its production and use |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103319558B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105906680A (en) * | 2016-04-27 | 2016-08-31 | 华润紫竹药业有限公司 | Desogestrel preparation method and midbody compound |
CN111362996A (en) * | 2020-04-26 | 2020-07-03 | 梯尔希(南京)药物研发有限公司 | Preparation method of gestodene impurity F |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN86102560A (en) * | 1985-05-10 | 1987-01-21 | 施林工业产权保护股份公司 | 17 α-ethynyl-17 beta-hydroxies-18-methyl-4, the preparation method of 15-estradiene-3-ketone |
EP1586579A1 (en) * | 2004-03-08 | 2005-10-19 | POLI INDUSTRIA CHIMICA S.p.A. | Process for the preparation of delta(15-16)-17-ketosteroids and use thereof in the synthesis of pharmacologically active compounds |
WO2011098439A2 (en) * | 2010-02-09 | 2011-08-18 | Laboratoire Theramex | A process for introducing a double bond into position 15,16 of a steroid |
-
2012
- 2012-03-22 CN CN201210077607.0A patent/CN103319558B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN86102560A (en) * | 1985-05-10 | 1987-01-21 | 施林工业产权保护股份公司 | 17 α-ethynyl-17 beta-hydroxies-18-methyl-4, the preparation method of 15-estradiene-3-ketone |
EP1586579A1 (en) * | 2004-03-08 | 2005-10-19 | POLI INDUSTRIA CHIMICA S.p.A. | Process for the preparation of delta(15-16)-17-ketosteroids and use thereof in the synthesis of pharmacologically active compounds |
WO2011098439A2 (en) * | 2010-02-09 | 2011-08-18 | Laboratoire Theramex | A process for introducing a double bond into position 15,16 of a steroid |
Non-Patent Citations (1)
Title |
---|
李丽等: "孕二烯酮的合成方法研究", 《化工中间体》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105906680A (en) * | 2016-04-27 | 2016-08-31 | 华润紫竹药业有限公司 | Desogestrel preparation method and midbody compound |
CN111362996A (en) * | 2020-04-26 | 2020-07-03 | 梯尔希(南京)药物研发有限公司 | Preparation method of gestodene impurity F |
Also Published As
Publication number | Publication date |
---|---|
CN103319558B (en) | 2016-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3562260A (en) | 2-carbonyl-estratrienes and method of their preparation | |
US8450476B2 (en) | Process for the preparation of 17-hydroxy-6β,7β;15β,16β-bismethylene-17α-pregn-4-ene-3-one-21-carboxylic acid γ-lactone and key intermediates for this process | |
CN102134265B (en) | Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone | |
CN101061133B (en) | Industrial method for preparing 17- hydroxy- 6beta, 7beta, 15beta, 16beta- bisacrylamide- 3- oxo- 17alpha- pregnane- 4- ene- 3- ketone- 21- carboxylate gamma- lactone and key intermediate used for the | |
CN100480256C (en) | Method for synthesizing Drospirenone | |
MX2008016571A (en) | A process for preparing drospirenone and intermediate thereof. | |
CN104262442A (en) | Preparation method for progestin | |
CN102875629B (en) | Synthetic method of ulipristal acetate | |
CN103319558B (en) | Steroidal compounds and its production and use | |
CN102964419A (en) | Preparation method of compound dienogest | |
US20040024202A1 (en) | C-17 spirolactonization and 6,7 oxidation of steroids | |
CN104926906A (en) | Method for preparing 17alpha-hydroxyl progesterone | |
CN101434632A (en) | Preparation of 3 alpha, 7 alpha-dihydroxy-5 beta-cholanic acid | |
CN103130862B (en) | The synthetic method of two (ethylenedioxy)-19-norpregna-5, the 9-diene-17-alcohol of CDB-2914 key intermediate 3,20- | |
CN101560237A (en) | 14beta-hydro6beta,7beta,15beta,16beta-dimethylene-3-oxo-17beta-pregn-4-ene-21,17-carbolactone and synthesis method thereof | |
JP5898731B2 (en) | Process for producing 17- (3-hydroxypropyl) -17-hydroxysteroid | |
DE2417846A1 (en) | 7-POSITION SUBSTITUTED STEROIDS OF THE OESTRAN SERIES | |
CN103421070A (en) | Improved pregnane alkene compound C21-acetoxylation method | |
CN105906680A (en) | Desogestrel preparation method and midbody compound | |
KR100639655B1 (en) | Process for preparing 4,1720-prostadien-3,16-dione from 16?,17?-epoxypregnenolone and the intermediate compounds for preparing the same | |
CN105481924B (en) | A kind of preparation method of progesterone | |
CN104109185A (en) | Preparation method of abiraterone acetate | |
CN101704871B (en) | Steroid compound and application thereof | |
CN105237605B (en) | A kind of intermediate and its preparation method and application for synthesizing gestodene | |
Shen et al. | The first synthesis of Krempene B |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
CB02 | Change of applicant information |
Address after: 100024 No. 27 Chaoyang North Road, Beijing, Chaoyang District Applicant after: CHINA?RESOURCES?ZIZHU?PHARMACEUTICAL?CO., LTD. Address before: 100024 No. 27 Chaoyang North Road, Beijing, Chaoyang District Applicant before: Zizhu Pharmaceutical Co., Ltd., Beijing |
|
CB02 | Change of applicant information | ||
COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: ZIZHU PHARMACEUTICAL CO., LTD., BEIJING TO: HUARUN ZIZHU PHARMACEUTICAL CO., LTD. |
|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |