CN103319558B - Steroidal compounds and its production and use - Google Patents
Steroidal compounds and its production and use Download PDFInfo
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- CN103319558B CN103319558B CN201210077607.0A CN201210077607A CN103319558B CN 103319558 B CN103319558 B CN 103319558B CN 201210077607 A CN201210077607 A CN 201210077607A CN 103319558 B CN103319558 B CN 103319558B
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- 0 CC[C@](CC1)(C(C[C@]2*)C3C1C(CCC(OCC)=C1)C1=CC3)C2=O Chemical compound CC[C@](CC1)(C(C[C@]2*)C3C1C(CCC(OCC)=C1)C1=CC3)C2=O 0.000 description 2
- BKWWXJJWAQPJFB-HSIWFZMLSA-N CC[C@](CC1)(C(CC2)C3C1C(CCC(OCC)=C1)C1=CC3)C2=O Chemical compound CC[C@](CC1)(C(CC2)C3C1C(CCC(OCC)=C1)C1=CC3)C2=O BKWWXJJWAQPJFB-HSIWFZMLSA-N 0.000 description 1
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Abstract
Intermediate that the invention provides gestodene and preparation method thereof, provides a kind of operational path preparing gestodene newly simultaneously.By introducing benzenesulfinyl to 16 of steroidal etherate, obtain a kind of new compound being easy to be separated, this compound is for the preparation of simple to operate during gestodene and yield is higher.
Description
Technical field
The present invention relates to steroidal compounds and preparing the application in gestodene process.
Background technology
Gestodene is third generation contraceptive bian ideal at present, and its progestogen action is strong, and without male sex hormone and estrogen activity.Reliable for effect when this medicine is for practising contraception, security good, the composite sheet of existing clinical conventional itself and ethinylestradiol is as Short-term effective oral contraceptives.
Patent EP1586579 discloses a kind of synthetic method of gestodene; this method with ethyl diketone compound (I) for starting raw material; by carrying out ketal protection to 3 carbonyls; then 16 reactive hydrogens are replaced; eliminate substituting group and form 15 (16) position double bonds; again through 17 carbonyl ethinylations, last 3 deprotections obtain gestodene (V), its reaction process as shown in Scheme 1:
[route 1]
The shortcoming of above-mentioned preparation method is mainly: 16-benzenesulfinyl Betamethasone Ketal structures (VII) is oily mixture, can only be separated, be unfavorable for suitability for industrialized production by the method for column chromatography; Ketal protected group not easily leaves away, and when deprotection prepares gestodene under acid conditions, yield is lower.
Summary of the invention
An object of the present invention is for providing a kind of new steroidal compounds, and the preparation method of this compound.
Two of object of the present invention is preparing the purposes in gestodene process for providing this steroidal compounds.
New steroidal compounds, its structural formula is as follows:
Compound III reacts obtained by the pregnant steroid-3 (4), 5 of 3-oxyethyl group-13 β-ethyl (6)-diene-17-ketone (II) and benzene sulfurous acid methyl esters.
Compound II per is obtained by the etherification protection of ethyl diketone compound (I) by 3 carbonyls.
Compound I commercially can be bought 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 preparing gestodene, and method disclosed in document EP2354150 can be adopted to prepare gestodene further by compound IV.
Specifically, above-mentioned steps of the present invention can be realized by following reaction:
1) 16 reactive hydrogens of Compound II per replace, and obtain compound III:
Compound II per and organic solvent are joined in reaction vessel, adds alkali, react 0.5 ~ 1 hour at 15-30 DEG C of temperature, add benzene sulfurous acid methyl esters again, after tlc detection reaction is complete, add purified water, separate out a large amount of yellow solid, then filter, dry to obtain compound III.Wherein, described organic solvent is selected from tetrahydrofuran (THF), 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 reaction vessel, at 15 ~ 30 DEG C of temperature, adds alkali, be then slowly warming up to solvent reflux temperature, and continue to add alkali at interval of 0.5 ~ 1.5h, reaction 4 ~ 6h, after tlc detection reaction is complete, concentrates and to obtain faint yellow solid IV crude product.Finally to above-mentioned crude product normal pressure column chromatography for separation, dry after merging target product, obtain 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, apply steroidal compounds of the present invention and prepare the simple for process of gestodene and yield is higher.
2, the 16-benzenesulfinyl etherate (III) prepared directly is separated by the method for elutriation; overcoming 16-benzenesulfinyl Betamethasone Ketal structures of the prior art can only by the shortcoming of column chromatography for separation; be not only applicable to laboratory study, be more conducive to industrialized amplification and produce.
Embodiment
Embodiment 1: the preparation of Compound II per
Compound I 10g (34.92mmol) and 10mL dehydrated alcohol stir under room temperature (17 DEG C), add triethyl orthoformate 10ml and tosic acid 0.2g, after stirring reaction 1h, and stopped reaction.Carry out column chromatography for separation by ethyl acetate/petroleum ether (2: 8), obtained product (Compound II per) weight is 7.28g, and molar yield is 80.0%.
Embodiment 2: the preparation of compound III
Compound II per 7g (22.26mmol) mixes with 100mL tetrahydrofuran (THF), adds potassium tert.-butoxide 8.51g under room temperature (15 DEG C), adds benzene sulfurous acid methyl esters 10mL under stirring, after stirring reaction 2h, and stopped reaction.Elutriation obtains yellow solid (compound III), dries rear heavy 7.32g, and molar yield is 69.5%.
MS (m/z): 438 [M] of compound III+, 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 II per 7g (22.26mmol) mixes with 100mL methylene dichloride, adds potassium hydroxide 3.50g under room temperature (20 DEG C), adds benzene sulfurous acid methyl esters 10mL under stirring, after stirring reaction 2h, and stopped reaction.Elutriation obtains yellow solid (compound III), dries rear heavy 6.88g, and molar yield is 65.3%.
MS (m/z): 438 [M] of compound III
+, 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 II per 7g (22.26mmol) mixes with 100mLN, dinethylformamide, adds potassium tert.-butoxide 8.51g under room temperature (30 DEG C), adds benzene sulfurous acid methyl esters 10mL under stirring, after stirring reaction 2h, and stopped reaction.Elutriation obtains yellow solid (compound III), dries rear heavy 6.95g, and molar yield is 66.0%.
MS (m/z): 438 [M] of compound III
+, 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 140mL toluene solution, adds 14mL triethylamine, be slowly warming up to backflow under room temperature (15 DEG C), continues reaction, adds 14mL triethylamine, constantly stir, react completely after 5h at interval of 1h.Concentrated for reaction solution rear ethyl acetate/petroleum ether (2: 8) is carried out column chromatography for separation, and finally obtain 4.41g product (compound IV), molar yield is 88.2%.
Embodiment 6: the preparation of compound IV
Compound III 7g (15.96mmol) mixes with 140mL benzole soln, adds 8mL quadrol, be slowly warming up to backflow under room temperature (30 DEG C), continues reaction, adds 8mL quadrol, constantly stir, react completely after 5h at interval of 1h.Concentrated for reaction solution rear ethyl acetate/petroleum ether (2: 8) is carried out column chromatography for separation, and finally obtain 3.86g product (compound IV), molar yield is 77.2%.
Claims (8)
1. a steroidal compounds, its structure is shown below:
2. the preparation method of steroidal compounds according to claim 1, is characterized by Compound II per: 3-oxyethyl group-13 β-ethyl pregnant steroid-3 (4), 5 (6)-diene-17-ketone and benzene sulfurous acid methyl esters react obtained.
3. preparation method according to claim 2, is characterized by reaction and adds highly basic, and organic solvent is selected from tetrahydrofuran (THF), methylene dichloride, N, dinethylformamide, ether and methyl-tert butanols ether.
4. preparation method according to claim 3, is characterized by highly basic used 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 according to claim 1, is characterized by for the preparation of gestodene.
6. purposes according to claim 5, it is characterized by the midbody compound IV of compound III for the preparation of gestodene, the structure of compound IV is shown below:
7. purposes according to claim 6, is characterized by preparation feedback and adds alkali, and organic solvent is selected from toluene, dimethylbenzene and dithiocarbonic anhydride.
8. purposes according to claim 7, is characterized by alkali used and is selected from triethylamine, diethylamine, Tetramethyl Ethylene Diamine, n-Butyl Amine 99, hexahydroaniline, Tributylamine and quadrol.
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| CN201210077607.0A CN103319558B (en) | 2012-03-22 | 2012-03-22 | Steroidal compounds and its production and use |
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Families Citing this family (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 |
|---|
| 孕二烯酮的合成方法研究;李丽等;《化工中间体》;20101231(第11期);42-44 * |
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